The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Margaret A. Vizzard - One of the best experts on this subject based on the ideXlab platform.
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Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)
Journal of Molecular Neuroscience, 2020Co-Authors: Beatrice M. Girard, Victor May, Harrison Hsiang, Susan E. Campbell, Katharine I. Beca, Megan Perkins, Margaret A. VizzardAbstract:Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP ( Adcyap1 ) and PAC1 receptor ( ADCYAP1R1 ) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly ( p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly ( p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly ( p ≤ 0.01) increased infused volume (1.5–2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly ( p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.
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PACAP/PAC1 Expression and Function in Micturition Pathways
Journal of Molecular Neuroscience, 2019Co-Authors: Jacqueline Ojala, Beatrice M. Girard, Katharine Tooke, Harrison Hsiang, Margaret A. VizzardAbstract:Neural injury, inflammation, or diseases commonly and adversely affect micturition reflex function that is organized by neural circuits in the CNS and PNS. One neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1 ), and its cognate receptor, PAC1 ( ADCYAP1R1 ), have tissue-specific distributions in the lower urinary tract. PACAP and associated receptors are expressed in the LUT and exhibit changes in expression, distribution, and function in preclinical animal models of bladder pain syndrome (BPS)/interstitial cystitis (IC), a chronic, visceral pain syndrome characterized by pain, and LUT dysfunction. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency and somatic (e.g., hindpaw, pelvic) sensitivity in preclinical animal models and a transgenic mouse model that mirrors some clinical symptoms of BPS/IC. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction following urinary bladder inflammation.
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PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca^2+ Activity in Urothelial Cells from Mice
Journal of Molecular Neuroscience, 2019Co-Authors: Thomas J. Heppner, Grant W. Hennig, Mark T. Nelson, Margaret A. VizzardAbstract:Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1 ) and its cognate PAC1 receptor ( ADCYAP1R1 ) have tissue-specific distributions in the lower urinary tract (LUT). The afferent limb of the micturition reflex is often compromised following bladder injury, disease, and inflammatory conditions. We have previously demonstrated that PACAP signaling contributes to increased voiding frequency and decreased bladder capacity with cystitis. Thus, the present studies investigated the sensory components (e.g., urothelial cells, bladder afferent nerves) of the urinary bladder that may underlie the pathophysiology of aberrant PACAP activation. We utilized bladder-pelvic nerve preparations and urothelial sheet preparations to characterize PACAP-induced bladder afferent nerve discharge with distention and PACAP-induced Ca^2+ activity, respectively. We determined that PACAP38 (100 nM) significantly ( p ≤ 0.01) increased bladder afferent nerve activity with distention that was blocked with a PAC1/VPAC2 receptor antagonist PACAP6-38 (300 nM). PACAP38 (100 nM) also increased Ca^2+ activity in urothelial cells over that observed in control preparations. Taken together, these results establish a role for PACAP signaling in bladder sensory components (e.g., urothelial cells, bladder afferent nerves) that may ultimately facilitate increased voiding frequency.
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PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca2+ Activity in Urothelial Cells from Mice.
Journal of molecular neuroscience : MN, 2018Co-Authors: Thomas J. Heppner, Victor May, Grant W. Hennig, Mark Nelson, Margaret A. VizzardAbstract:Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (ADCYAP1R1) have tissue-specific distributions in the lower urinary tract (LUT). The afferent limb of the micturition reflex is often compromised following bladder injury, disease, and inflammatory conditions. We have previously demonstrated that PACAP signaling contributes to increased voiding frequency and decreased bladder capacity with cystitis. Thus, the present studies investigated the sensory components (e.g., urothelial cells, bladder afferent nerves) of the urinary bladder that may underlie the pathophysiology of aberrant PACAP activation. We utilized bladder-pelvic nerve preparations and urothelial sheet preparations to characterize PACAP-induced bladder afferent nerve discharge with distention and PACAP-induced Ca2+ activity, respectively. We determined that PACAP38 (100 nM) significantly (p ≤ 0.01) increased bladder afferent nerve activity with distention that was blocked with a PAC1/VPAC2 receptor antagonist PACAP6-38 (300 nM). PACAP38 (100 nM) also increased Ca2+ activity in urothelial cells over that observed in control preparations. Taken together, these results establish a role for PACAP signaling in bladder sensory components (e.g., urothelial cells, bladder afferent nerves) that may ultimately facilitate increased voiding frequency.
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PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress
Frontiers in systems neuroscience, 2017Co-Authors: Beatrice M. Girard, Katharine Tooke, Margaret A. VizzardAbstract:Complex organization of CNS and PNS pathways is necessary for the coordinated and reciprocal functions of the urinary bladder, urethra and urethral sphincters. Injury, inflammation, psychogenic stress or diseases that affect these nerve pathways and target organs can produce lower urinary tract (LUT) dysfunction. Numerous neuropeptide/receptor systems are expressed in the neural pathways of the LUT and non-neural components of the LUT (e.g., urothelium) also express peptides. One such neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate receptor, PAC1 (ADCYAP1R1), have tissue-specific distributions in the LUT. Mice with a genetic deletion of PACAP exhibit bladder dysfunction and altered somatic sensation. PACAP and associated receptors are expressed in the LUT and exhibit neuroplastic changes with neural injury, inflammation, and diseases of the LUT as well as psychogenic stress. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency in preclinical animal models and transgenic mouse models that mirror some clinical symptoms of bladder dysfunction. A change in the balance of the expression and resulting function of the PACAP/receptor system in CNS and PNS bladder reflex pathways may underlie LUT dysfunction including symptoms of urinary urgency, increased voiding frequency, and visceral pain. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction.
Victor May - One of the best experts on this subject based on the ideXlab platform.
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PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability
Journal of Molecular Neuroscience, 2021Co-Authors: Victor May, Karen M. Braas, Sayamwong E Hammack, Gregory C. Johnson, Rodney L. ParsonsAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1 ) activation of PAC1 receptors ( ADCYAP1R1 ) can significantly increase the excitability of diverse neurons through differential mechanisms. For guinea pig cardiac neurons, the modulation of excitability can be mediated in part by PAC1 receptor plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. By contrast, PAC1 receptor-mediated excitability of hippocampal dentate gyrus granule cells appears independent of membrane-delimited AC/cAMP/PKA and PLC/PKC signaling. For both neuronal types, there is mechanistic convergence demonstrating that endosomal PAC1 receptor signaling has prominent roles. In these models, neuronal exposure to Pitstop2 to inhibit β-arrestin/clathrin-mediated PAC1 receptor internalization eliminates PACAP modulation of excitability. β-arrestin is a scaffold for a number of effectors especially MEK/ERK and notably, paradigms that inhibit PAC1 receptor endosome formation and ERK signaling also blunt the PACAP-induced increase in excitability. Detailed PAC1 receptor internalization and endosomal ERK signaling mechanisms have been confirmed in HEK PAC1R-EGFP cells and shown to be long lasting which appear to recapitulate the sustained electrophysiological responses. Thus, PAC1 receptor internalization/endosomal recruitment efficiently and efficaciously activates MEK/ERK signaling and appears to represent a singular and critical common denominator in regulating neuronal excitability by PACAP.
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Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)
Journal of Molecular Neuroscience, 2020Co-Authors: Beatrice M. Girard, Victor May, Harrison Hsiang, Susan E. Campbell, Katharine I. Beca, Megan Perkins, Margaret A. VizzardAbstract:Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP ( Adcyap1 ) and PAC1 receptor ( ADCYAP1R1 ) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly ( p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly ( p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly ( p ≤ 0.01) increased infused volume (1.5–2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly ( p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.
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The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in the Hippocampal Dentate Gyrus.
Frontiers in cellular neuroscience, 2020Co-Authors: Gregory C. Johnson, Rodney L. Parsons, Victor May, Sayamwong E HammackAbstract:Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) dysregulation has been associated with multiple stress-related psychopathologies that may be related to altered hippocampal function. In coherence, PACAP- and PAC1 receptor (ADCYAP1R1)-null mice demonstrate changes in hippocampal-dependent behavioral responses, implicating the PACAPergic system function in this structure. Within the hippocampus, the dentate gyrus (DG) may play an important role in discerning the differences between similar contexts, and DG granule cells appear to both highly express PAC1 receptors and receive inputs from PACAP-expressing terminals. Here, we review the evidence from our laboratories and others that PACAP is an important regulator of activity within hippocampal circuits, particularly within the DG. These data are consistent with an increasing literature implicating PACAP circuits in stress-related pathologies such as post-traumatic stress disorder (PTSD) and implicate the hippocampus, and in particular the DG, as a critical site in which PACAP dysregulation can alter stress-related behaviors.
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Pituitary adenylate cyclase-activating polypeptide-induced PAC1 receptor internalization and recruitment of MEK/ERK signaling enhance excitability of dentate gyrus granule cells.
American journal of physiology. Cell physiology, 2020Co-Authors: Gregory C. Johnson, Rodney L. Parsons, Victor May, Sayamwong E HammackAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP; ADCYAP1) is a pleiotropic neuropeptide widely distributed in both the peripheral and central nervous systems. PACAP and its specific cognate PAC1 receptor (ADCYAP1R1) play critical roles in the homeostatic maintenance of multiple physiological and behavioral systems. Notably, maladaptations in the PACAPergic system have been associated with several psychopathologies related to fear and anxiety. PAC1 receptor transcripts are highly expressed in granule cells of the dentate gyrus (DG). Here, we examined the direct effects of PACAP on DG granule cells in brain slices using whole cell patch recordings in current clamp mode. PACAP significantly increased the intrinsic excitability of DG granule cells via PAC1 receptor activation. This increased excitability was not mediated by adenylyl cyclase/cAMP or phospholipase C/PKC activation, but instead via activation of an extracellular signal-regulated kinase (ERK) signaling pathway initiated through PAC1 receptor endocytosis/endosomal signaling. PACAP failed to increase excitability in DG granule cells pretreated with the persistent sodium current blocker riluzole, suggesting that the observed PACAP effects required this component of the inward sodium current.
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PAC1 Receptors: Shapeshifters in Motion
Journal of Molecular Neuroscience, 2019Co-Authors: Chenyi Liao, Victor MayAbstract:Shapeshifters, in common mythology, are entities that can undergo multiple physical transformations. As our understanding of G protein-coupled receptors (GPCRs) has accelerated and been refined over the last two decades, we now understand that GPCRs are not static proteins, but rather dynamic structures capable of moving from one posture to the next, and adopting unique functional characteristics at each transition. This model of GPCR dynamics underlies our current understanding of biased agonism—how different ligands to the same receptor can generate different intracellular signals—and constitutive receptor activity, or the level of unbound basal receptor signaling that can be attenuated by inverse agonists. From information derived from related class B receptors, we have recently modeled the structure and molecular dynamics of the full-length pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1 )—selective PAC1 receptor (PAC1R, ADCYAP1R1 ). The class B receptors are different from the class A GPCRs in part from the presence of a large extracellular domain (ECD); the transitions of the ECD along with the dynamics of the transmembrane domains (TMD or 7TM) of the PAC1R describes a series of open- and closed-state conformations that appear to identify the mechanisms for receptor activation. The PAC1R shapeshifts also have the ability of delineating the mechanisms and the design of reagents that may direct biased agonism (or antagonism) for potential therapeutics.
Kerry J Ressler - One of the best experts on this subject based on the ideXlab platform.
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parabrachial pituitary adenylate cyclase activating polypeptide activation of amygdala endosomal extracellular signal regulated kinase signaling regulates the emotional component of pain
Biological Psychiatry, 2017Co-Authors: Galen Missig, Karen M. Braas, Margaret A. Vizzard, Kerry J Ressler, James A. Waschek, Sayamwong E HammackAbstract:Abstract Background Chronic pain and stress-related psychopathologies, such as depression and anxiety-associated abnormalities, are mutually reinforcing; however, the neuronal circuits and mechanisms that underlie this reinforcement are still not well understood. Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1 ) and its cognate PAC1 receptor ( ADCYAP1R1 ) are expressed in peripheral nociceptive pathways, participate in anxiety-related responses and have been have been linked to posttraumatic stress disorder and other mental health afflictions. Methods Using immunocytochemistry, pharmacological treatments and behavioral testing techniques, we have used a rodent partial sciatic nerve chronic constriction injury model ( n = 5–8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive and stress-related behaviors. Results We show that chronic neuropathic pain increases PACAP expression at multiple tiers along the spinoparabrachioamygdaloid tract. Furthermore, chronic constriction injury bilaterally augments nociceptive amygdala (in the central nucleus of the amygdala [CeA]) PACAP immunoreactivity, extracellular signal–regulated kinase phosphorylation, and c-Fos activation, in parallel with heightened anxiety-like behavior and nociceptive hypersensitivity. Acute CeA infusions with the PACAP receptor antagonist PACAP(6-38) blocked chronic constriction injury–induced behavioral responses. Additionally, pretreatments with inhibitors of mitogen-activated protein kinase enzymes or endocytosis to block endosomal PACAP receptor extracellular signal–regulated kinase signaling attenuated PACAP-induced CeA neuronal activation and nociceptive responses. Conclusions Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in spinoparabrachioamygdaloid projections have an impact on CeA stress- and nociception-associated maladaptive responses, which can be ameliorated upon receptor antagonism even during injury progression. Thus, the PACAP pathway provides for an important mechanism underlying the intersection of stress and chronic pain pathways via the amygdala.
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Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal–Regulated Kinase Signaling Regulates the Emotional Component of Pain
Biological psychiatry, 2016Co-Authors: Galen Missig, Karen M. Braas, Margaret A. Vizzard, Sayamwong E Hammack, Kerry J Ressler, James A. Waschek, Linda Mei, Victor MayAbstract:Abstract Background Chronic pain and stress-related psychopathologies, such as depression and anxiety-associated abnormalities, are mutually reinforcing; however, the neuronal circuits and mechanisms that underlie this reinforcement are still not well understood. Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1 ) and its cognate PAC1 receptor ( ADCYAP1R1 ) are expressed in peripheral nociceptive pathways, participate in anxiety-related responses and have been have been linked to posttraumatic stress disorder and other mental health afflictions. Methods Using immunocytochemistry, pharmacological treatments and behavioral testing techniques, we have used a rodent partial sciatic nerve chronic constriction injury model ( n = 5–8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive and stress-related behaviors. Results We show that chronic neuropathic pain increases PACAP expression at multiple tiers along the spinoparabrachioamygdaloid tract. Furthermore, chronic constriction injury bilaterally augments nociceptive amygdala (in the central nucleus of the amygdala [CeA]) PACAP immunoreactivity, extracellular signal–regulated kinase phosphorylation, and c-Fos activation, in parallel with heightened anxiety-like behavior and nociceptive hypersensitivity. Acute CeA infusions with the PACAP receptor antagonist PACAP(6-38) blocked chronic constriction injury–induced behavioral responses. Additionally, pretreatments with inhibitors of mitogen-activated protein kinase enzymes or endocytosis to block endosomal PACAP receptor extracellular signal–regulated kinase signaling attenuated PACAP-induced CeA neuronal activation and nociceptive responses. Conclusions Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in spinoparabrachioamygdaloid projections have an impact on CeA stress- and nociception-associated maladaptive responses, which can be ameliorated upon receptor antagonism even during injury progression. Thus, the PACAP pathway provides for an important mechanism underlying the intersection of stress and chronic pain pathways via the amygdala.
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Genomic Regulation of the PACAP Receptor, PAC1, and Implications for Psychiatric Disease
Epigenetics and Neuroendocrinology, 2016Co-Authors: Kristina B Mercer, Kerry J ResslerAbstract:Impairment of the hypothalamic-pituitary-adrenal (HPA) axis and related neurological signaling has been attributed to several psychiatric conditions including unipolar and bipolar depression and posttraumatic stress disorder (PTSD). Consequently, irregularities in the mRNA expression or protein levels of neuropeptide hormones and receptors involved in related stress pathways can trigger these neurological disorders. As a critical modulator of the stress and fear pathways in concert with the pituitary adenylate cyclase-activating peptide (PACAP) ligand, the PAC1 receptor (PAC1) has been implicated in risk for PTSD. Genetic variants, epigenetic alterations, and hormone regulation have been attributed to changes in the expression of ADCYAP1R1 which encodes the PAC1 protein. The chapter will focus on a review of PACAP-induced cellular function, localization, and expression of the PAC1 receptor. The goal of this review is to address the effects of altered expression of PAC1 on phenotypic outcomes, particularly those neurological in nature. We also discuss existing and potential mechanisms that can induce changes in ADCYAP1R1 transcript levels, including genetic and epigenetic alterations and hormone regulation.
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gene by social environment interaction gxse between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma exposed women
Journal of Affective Disorders, 2015Co-Authors: Sarah R Lowe, Kerry J Ressler, Sandro Galea, Bekh Bradley, John Pothen, James W Quinn, Andrew Rundle, Karestan C KoenenAbstract:Background Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women.
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Early Intervention Following Trauma May Mitigate Genetic Risk for PTSD in Civilians: A Pilot Prospective Emergency Department Study
The Journal of clinical psychiatry, 2014Co-Authors: Barbara O. Rothbaum, Kristina B Mercer, Kimberly Kerley, Emily Reiser, Jennifer S. Davis, Megan C. Kearns, Alex O. Rothbaum, Matthew Price, Debra E. Houry, Kerry J ResslerAbstract:BACKGROUND: Civilian posttraumatic stress disorder (PTSD) and combat PTSD are major public health concerns. Although a number of psychosocial risk factors have been identified related to PTSD risk, there are no accepted, robust biological predictors that identify who will develop PTSD or who will respond to early intervention following trauma. We wished to examine whether genetic risk for PTSD can be mitigated with an early intervention. METHOD: 65 emergency department patients recruited in 2009-2010 at Grady Memorial Hospital in Atlanta, Georgia, who met criterion A of DSM-IV PTSD received either 3 sessions of an exposure intervention, beginning in the emergency department shortly after trauma exposure or assessment only. PTSD symptoms were assessed 4 and 12 weeks after trauma exposure. A composite additive risk score was derived from polymorphisms in 10 previously identified genes associated with stress-response (ADCYAP1R1, COMT, CRHR1, DBH, DRD2, FAAH, FKBP5, NPY, NTRK2, and PCLO), and gene x treatment effects were examined. The intervention included 3 sessions of imaginal exposure to the trauma memory and additional exposure homework. The primary outcome measure was the PTSD Symptom Scale-Interview Version or DSM-IV-based PTSD diagnosis in patients related to genotype and treatment group. RESULTS: A gene x intervention x time effect was detected for individual polymorphisms, in particular the PACAP receptor, ADCYAP1R1, as well as with a combined genotype risk score created from independent SNP markers. Subjects who did not receive treatment had higher symptoms than those who received intervention. Furthermore, subjects with the "risk" genotypes who did not receive intervention had higher PTSD symptoms compared to those with the "low-risk" or "resilience" genotypes or those who received intervention. Additionally, PTSD symptoms correlated with level of genetic risk at week 12 (P CONCLUSIONS: This pilot prospective study suggests that combined genetic variants may serve to predict those most at risk for developing PTSD following trauma. A psychotherapeutic intervention initiated in the emergency department within hours of the trauma may mitigate this risk. The role of genetic predictors of risk and resilience should be further evaluated in larger, prospective intervention and prevention trials.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00895518. Language: en
Beatrice M. Girard - One of the best experts on this subject based on the ideXlab platform.
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Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)
Journal of Molecular Neuroscience, 2020Co-Authors: Beatrice M. Girard, Victor May, Harrison Hsiang, Susan E. Campbell, Katharine I. Beca, Megan Perkins, Margaret A. VizzardAbstract:Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP ( Adcyap1 ) and PAC1 receptor ( ADCYAP1R1 ) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly ( p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly ( p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly ( p ≤ 0.01) increased infused volume (1.5–2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly ( p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.
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PACAP/PAC1 Expression and Function in Micturition Pathways
Journal of Molecular Neuroscience, 2019Co-Authors: Jacqueline Ojala, Beatrice M. Girard, Katharine Tooke, Harrison Hsiang, Margaret A. VizzardAbstract:Neural injury, inflammation, or diseases commonly and adversely affect micturition reflex function that is organized by neural circuits in the CNS and PNS. One neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1 ), and its cognate receptor, PAC1 ( ADCYAP1R1 ), have tissue-specific distributions in the lower urinary tract. PACAP and associated receptors are expressed in the LUT and exhibit changes in expression, distribution, and function in preclinical animal models of bladder pain syndrome (BPS)/interstitial cystitis (IC), a chronic, visceral pain syndrome characterized by pain, and LUT dysfunction. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency and somatic (e.g., hindpaw, pelvic) sensitivity in preclinical animal models and a transgenic mouse model that mirrors some clinical symptoms of BPS/IC. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction following urinary bladder inflammation.
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PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress
Frontiers in systems neuroscience, 2017Co-Authors: Beatrice M. Girard, Katharine Tooke, Margaret A. VizzardAbstract:Complex organization of CNS and PNS pathways is necessary for the coordinated and reciprocal functions of the urinary bladder, urethra and urethral sphincters. Injury, inflammation, psychogenic stress or diseases that affect these nerve pathways and target organs can produce lower urinary tract (LUT) dysfunction. Numerous neuropeptide/receptor systems are expressed in the neural pathways of the LUT and non-neural components of the LUT (e.g., urothelium) also express peptides. One such neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate receptor, PAC1 (ADCYAP1R1), have tissue-specific distributions in the LUT. Mice with a genetic deletion of PACAP exhibit bladder dysfunction and altered somatic sensation. PACAP and associated receptors are expressed in the LUT and exhibit neuroplastic changes with neural injury, inflammation, and diseases of the LUT as well as psychogenic stress. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency in preclinical animal models and transgenic mouse models that mirror some clinical symptoms of bladder dysfunction. A change in the balance of the expression and resulting function of the PACAP/receptor system in CNS and PNS bladder reflex pathways may underlie LUT dysfunction including symptoms of urinary urgency, increased voiding frequency, and visceral pain. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction.
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Src family kinase inhibitors blunt PACAP-induced PAC1 receptor endocytosis, phosphorylation of ERK, and the increase in cardiac neuron excitability
American journal of physiology. Cell physiology, 2017Co-Authors: John D. Tompkins, Beatrice M. Girard, Laura A. Merriam, Jean C. Hardwick, Victor May, Todd A. Clason, Thomas R. Buttolph, Anne K. Linden, Rodney L. ParsonsAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (ADCYAP1R1) significantly increases excitability of guinea pig cardiac neurons. This modulation of e...
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Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability.
American journal of physiology. Cell physiology, 2016Co-Authors: John D. Tompkins, Beatrice M. Girard, Laura A. Merriam, Jean C. Hardwick, Victor May, Todd A. Clason, Rodney L. ParsonsAbstract:Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (ADCYAP1R1) participate in multiple homeostatic and stress-related respo...
Rodney L. Parsons - One of the best experts on this subject based on the ideXlab platform.
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PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability
Journal of Molecular Neuroscience, 2021Co-Authors: Victor May, Karen M. Braas, Sayamwong E Hammack, Gregory C. Johnson, Rodney L. ParsonsAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1 ) activation of PAC1 receptors ( ADCYAP1R1 ) can significantly increase the excitability of diverse neurons through differential mechanisms. For guinea pig cardiac neurons, the modulation of excitability can be mediated in part by PAC1 receptor plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. By contrast, PAC1 receptor-mediated excitability of hippocampal dentate gyrus granule cells appears independent of membrane-delimited AC/cAMP/PKA and PLC/PKC signaling. For both neuronal types, there is mechanistic convergence demonstrating that endosomal PAC1 receptor signaling has prominent roles. In these models, neuronal exposure to Pitstop2 to inhibit β-arrestin/clathrin-mediated PAC1 receptor internalization eliminates PACAP modulation of excitability. β-arrestin is a scaffold for a number of effectors especially MEK/ERK and notably, paradigms that inhibit PAC1 receptor endosome formation and ERK signaling also blunt the PACAP-induced increase in excitability. Detailed PAC1 receptor internalization and endosomal ERK signaling mechanisms have been confirmed in HEK PAC1R-EGFP cells and shown to be long lasting which appear to recapitulate the sustained electrophysiological responses. Thus, PAC1 receptor internalization/endosomal recruitment efficiently and efficaciously activates MEK/ERK signaling and appears to represent a singular and critical common denominator in regulating neuronal excitability by PACAP.
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The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in the Hippocampal Dentate Gyrus.
Frontiers in cellular neuroscience, 2020Co-Authors: Gregory C. Johnson, Rodney L. Parsons, Victor May, Sayamwong E HammackAbstract:Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) dysregulation has been associated with multiple stress-related psychopathologies that may be related to altered hippocampal function. In coherence, PACAP- and PAC1 receptor (ADCYAP1R1)-null mice demonstrate changes in hippocampal-dependent behavioral responses, implicating the PACAPergic system function in this structure. Within the hippocampus, the dentate gyrus (DG) may play an important role in discerning the differences between similar contexts, and DG granule cells appear to both highly express PAC1 receptors and receive inputs from PACAP-expressing terminals. Here, we review the evidence from our laboratories and others that PACAP is an important regulator of activity within hippocampal circuits, particularly within the DG. These data are consistent with an increasing literature implicating PACAP circuits in stress-related pathologies such as post-traumatic stress disorder (PTSD) and implicate the hippocampus, and in particular the DG, as a critical site in which PACAP dysregulation can alter stress-related behaviors.
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Pituitary adenylate cyclase-activating polypeptide-induced PAC1 receptor internalization and recruitment of MEK/ERK signaling enhance excitability of dentate gyrus granule cells.
American journal of physiology. Cell physiology, 2020Co-Authors: Gregory C. Johnson, Rodney L. Parsons, Victor May, Sayamwong E HammackAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP; ADCYAP1) is a pleiotropic neuropeptide widely distributed in both the peripheral and central nervous systems. PACAP and its specific cognate PAC1 receptor (ADCYAP1R1) play critical roles in the homeostatic maintenance of multiple physiological and behavioral systems. Notably, maladaptations in the PACAPergic system have been associated with several psychopathologies related to fear and anxiety. PAC1 receptor transcripts are highly expressed in granule cells of the dentate gyrus (DG). Here, we examined the direct effects of PACAP on DG granule cells in brain slices using whole cell patch recordings in current clamp mode. PACAP significantly increased the intrinsic excitability of DG granule cells via PAC1 receptor activation. This increased excitability was not mediated by adenylyl cyclase/cAMP or phospholipase C/PKC activation, but instead via activation of an extracellular signal-regulated kinase (ERK) signaling pathway initiated through PAC1 receptor endocytosis/endosomal signaling. PACAP failed to increase excitability in DG granule cells pretreated with the persistent sodium current blocker riluzole, suggesting that the observed PACAP effects required this component of the inward sodium current.
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PACAP-Induced PAC1 Receptor Internalization and Recruitment of Endosomal Signaling Regulate Cardiac Neuron Excitability
Journal of Molecular Neuroscience, 2019Co-Authors: Rodney L. ParsonsAbstract:Pituitary adenylate cyclase-activating polypeptide (PACAP, Adcyap1 ) activation of PAC1 receptors ( ADCYAP1R1 ) significantly increases excitability of guinea pig cardiac neurons. This modulation of excitability is mediated in part by plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades, as well as by endosomal signaling mechanisms. PACAP/PAC1 receptor-mediated activation of plasma membrane adenylyl cyclase (AC) and the resulting increase in cellular cAMP enhances a hyperpolarization-induced nonselective cationic current I _h, which contributes to the PACAP-induced increase in cardiac neuron excitability. Further, PACAP-mediated AC/cAMP/PKA downstream signaling also appears to enhance cardiac neuron I _T to facilitate the excitatory responses. PACAP activation of PAC1 receptors rapidly stimulates receptor internalization, and reducing ambient temperature or treatments with the clathrin inhibitor Pitstop2 or the dynamin I/II inhibitor dynasore to block endocytic events can suppress PACAP-enhanced neuronal excitability. Thus, endocytosis inhibitors essentially eliminate PACAP-enhanced excitability suggesting that endosomal platforms represent a primary signaling mechanism. Endosomal signaling is associated canonically with ERK activation and in accord, PACAP-enhanced cardiac neuron excitability is reduced by MEK inhibitor pretreatments. PACAP activation of MEK/ERK signaling can enhance currents through voltage-dependent Nav1.7 channels. Hence, PACAP-induced PAC1 receptor internalization/endosomal signaling, recruitment of MEK/ERK signaling, and modulation of Nav1.7 are implicated as key mechanisms contributing to the PACAP-enhanced neuronal excitability. PACAP/PAC1 receptor-mediated endosomal ERK signaling in central circuits can play key roles in development of chronic pain and anxiety-related responses; thus, PAC1 endosomal signaling likely participates in a variety of homeostatic responses within neuronal circuits in the CNS.
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Src family kinase inhibitors blunt PACAP-induced PAC1 receptor endocytosis, phosphorylation of ERK, and the increase in cardiac neuron excitability
American journal of physiology. Cell physiology, 2017Co-Authors: John D. Tompkins, Beatrice M. Girard, Laura A. Merriam, Jean C. Hardwick, Victor May, Todd A. Clason, Thomas R. Buttolph, Anne K. Linden, Rodney L. ParsonsAbstract:Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (ADCYAP1R1) significantly increases excitability of guinea pig cardiac neurons. This modulation of e...
