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Dane M. Chetkovich - One of the best experts on this subject based on the ideXlab platform.
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HCN Channels in the hippocampus regulate active coping behavior
Journal of Neurochemistry, 2018Co-Authors: Daniel W Fisher, Robert J Heuermann, Kyle A Lyman, Kendall M Foote, Linda A. Bean, Natividad Ybarra, Hongxin Dong, Daniel A. Nicholson, Dane M. ChetkovichAbstract:Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN Channels regulate neuronal excitability in pyramidal cells and that HCN Channel current (Ih ) in the CA1 area increases with chronic mild stress. Reduction of Ih in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of Ih is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN Channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN Channel expression. This approach led to a robust reduction in Ih in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN Channel function in CA1 influences coping style.
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HCN Channel dendritic targeting requires bipartite interaction with trip8b and regulates antidepressant like behavioral effects
Molecular Psychiatry, 2017Co-Authors: Robert J Heuermann, Kyle A Lyman, Daniel W Fisher, Quratul Ain Ismail, Dane M. ChetkovichAbstract:Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels regulate excitability in neurons, and blocking HCN Channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN Channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-Channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-Channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-Channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-Channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b–HCN interaction bidirectionally influences Channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.
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differential regulation of HCN Channel isoform expression in thalamic neurons of epileptic and non epileptic rat strains
Neurobiology of Disease, 2012Co-Authors: Tatyana Kanyshkova, Dane M. Chetkovich, Patrick Meuth, Hanschristian Pape, Pawan Bista, Petra Ehling, Luigi Caputi, Michael Doengi, Thomas BuddeAbstract:Abstract Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) Channels represent the molecular substrate of the hyperpolarization-activated inward current (Ih). Although these Channels act as pacemakers for the generation of rhythmic activity in the thalamocortical network during sleep and epilepsy, their developmental profile in the thalamus is not yet fully understood. Here we combined electrophysiological, immunohistochemical, and mathematical modeling techniques to examine HCN gene expression and Ih properties in thalamocortical relay (TC) neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in an epileptic (WAG/Rij) compared to a non-epileptic (ACI) rat strain. Recordings of TC neurons between postnatal day (P) 7 and P90 in both rat strains revealed that Ih was characterized by higher current density, more hyperpolarized voltage dependence, faster activation kinetics, and reduced cAMP-sensitivity in epileptic animals. All four HCN Channel isoforms (HCN1-4) were detected in dLGN, and quantitative analyses revealed a developmental increase of protein expression of HCN1, HCN2, and HCN4 but a decrease of HCN3. HCN1 was expressed at higher levels in WAG/Rij rats, a finding that was correlated with increased expression of the interacting proteins filamin A (FilA) and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Analysis of a simplified computer model of the thalamic network revealed that the alterations of Ih found in WAG/Rij rats compensate each other in a way that leaves Ih availability constant, an effect that ensures unaltered cellular burst activity and thalamic oscillations. These data indicate that during postnatal developmental the hyperpolarizing shift in voltage dependency (resulting in less current availability) is compensated by an increase in current density in WAG/Rij thereby possibly limiting the impact of Ih on epileptogenesis. Because HCN3 is expressed higher in young versus older animals, HCN3 likely does not contribute to alterations in Ih in older animals.
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the fast and slow ups and downs of HCN Channel regulation
Channels, 2010Co-Authors: Alan S. Lewis, Chad M. Estep, Dane M. ChetkovichAbstract:Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels (h Channels) form the molecular basis for the hyperpolarization-activated current, Ih, and modulation of h Channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h Channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, Channel conductance or subunit composition of h Channels. Here we provide a focused review examining mechanisms of h Channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in Ih in different biological models, as well as for molecular biologists to delineate the predicted h Channel changes associated with complex regulatory mechanisms in bo...
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The fast and slow ups and downs of HCN Channel regulation
Channels, 2010Co-Authors: Alan S. Lewis, Chad M. Estep, Dane M. ChetkovichAbstract:Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels (h Channels) form the molecular basis for the hyperpolarization-activated current, I(h), and modulation of h Channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h Channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, Channel conductance or subunit composition of h Channels. Here we provide a focused review examining mechanisms of h Channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in I(h) in different biological models, as well as for molecular biologists to delineate the predicted h Channel changes associated with complex regulatory mechanisms in both normal function and in disease states.
Bina Santoro - One of the best experts on this subject based on the ideXlab platform.
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HCN Channels: The Molecular Basis for their cAMP-TRIP8b Regulation
Biophysical Journal, 2015Co-Authors: Andrea Saponaro, Sofia R Pauleta, Francesca Cantini, Manolis Matzapetakis, Chiara Donadoni, Gerhard Thiel, Lucia Banci, Bina Santoro, Anna MoroniAbstract:Hyperpolarization-activated cyclic nucleotide-regulated (HCN1-4) Channels are involved in the regulation of several higher order neural functions, such as short- and long-term memory processes (1). HCN Channels are exquisitely sensitive to endogenous levels of cAMP, since they directly bind cAMP through a specialized domain in their cytoplasmic C-terminus (cyclic nucleotide binding domain, CNBD) (2). In addition to cAMP, HCN Channels are further regulated by TRIP8b, their brain-specific auxiliary subunit. TRIP8b antagonizes the effect of cAMP on HCN Channel opening, as it interacts with the CNBD of the Channel (3). We employed solution NMR methodologies to determine the 3D structure of the human HCN2 CNBD in the cAMP-free form, and mapped on it the TRIP8b interaction site. Thus, we were able to reconstruct, for the first time, the molecular mechanisms underlying the dual regulation of HCN Channel activity by cAMP-TRIP8b (4). Furthermore, site-directed mutagenesis followed by biochemical/biophysical analysis allowed us to identify key residues within the CNBD involved in TRIP8b binding. These new structural information will provide deeper insights into the molecular basis of neurological disorders associated with dysfunction of the HCN Channel conductance in neurons, potentially leading to the design of drugs able to modulate HCN Channel mediated memory processes.1) Nolan MF, Malleret G, Dudman JT, Buhl DL, Santoro B, Gibbs E, Vronskaya S, Buzsaki G, Siegelbaum SA, Kandel ER, Morozov A. (2004), Cell 119(5):719-732.2) Wainger BJ, DeGennaro M, Santoro B, Siegelbaum SA, Tibbs GR. (2001), Nature 411(6839):805-10.3) Hu L, Santoro B, Saponaro A, Liu H, Moroni A, Siegelbaum S. (2013), J Gen Physiol 142:599-612.4) Saponaro A, Pauleta SR, Cantini F, Matzapetakis M, Hammann C, Donadoni C, Hu L, Thiel G, Banci L, Santoro B, Moroni A. (2014), PNAS Sep 2. pii: 201410389. [Epub ahead of print].
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structural basis for the mutual antagonism of camp and trip8b in regulating HCN Channel function
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Andrea Saponaro, Sofia R Pauleta, Francesca Cantini, Manolis Matzapetakis, Christian Hammann, Chiara Donadoni, Lei Hu, Gerhard Thiel, Lucia Banci, Bina SantoroAbstract:cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN Channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the Channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN Channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 Channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN Channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN Channel CNBD.
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trip 8b ing up and down HCN Channel gating and trafficking
Biophysical Journal, 2014Co-Authors: Steven A Siegelbaum, Lei Hu, Bina SantoroAbstract:The proper neuronal functioning of ion Channels depends on their correct targeting to distinct polarized neuronal compartments, where the Channels often mediate highly specific functions. HCN1 Channels, which underlie the hyperpolarization-activated cation current (Ih) in many types of neurons, are targeted to the distal apical dendrites of hippocampal CA1 pyramidal neurons, where they regulate the integration of synaptic inputs and control excitability. Results from our laboratory and others indicate that the cytoplasmic protein TRIP8b is the major auxiliary subunit of HCN1 Channels in the brain, where it plays an important role in regulating HCN1 function, expression and localization. TRIP8b undergoes extensive alternative splicing at its N-terminus, with at least 10 splice variants detected in brain. All splice variants interact strongly with the C-terminus of all four HCN Channel isoforms (HCN1-4) at two different interaction surfaces. Whereas all TRIP8b isoforms inhibit Channel gating by antagonizing the normal action of cAMP to facilitate opening, the various isoforms have distinct effects on Channel trafficking. We identified two splice isoforms with opposing actions on HCN1 surface expression and distinct subcellular locales that are critical for HCN1 dendritic targeting. Our more recent results have identified the structural and functional bases for many of the regulatory actions of TRIP8b.
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regulation of HCN Channel surface expression by a novel c terminal protein protein interaction
The Journal of Neuroscience, 2004Co-Authors: Bina Santoro, Brian J Wainger, Steven A SiegelbaumAbstract:Hyperpolarization-activated cation currents (Ih) are carried by Channels encoded by a family of four genes (HCN1-4) that are differentially expressed within the brain in specific cellular and subcellular compartments. HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of Ih. Expression of Ih is also regulated by neuronal activity. To isolate proteins that may control HCN Channel expression or function, we performed yeast two-hybrid screens using the C-terminal cytoplasmic tails of the HCN proteins as bait. We identified a brain-specific protein, which has been previously termed TRIP8b (for TPR-containing Rab8b interacting protein) and PEX5Rp (for Pex5p-related protein), that specifically interacts with all four HCN Channels through a conserved sequence in their C-terminal tails. In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons. The dendritic expression of TRIP8b in layer V pyramidal neurons is disrupted after deletion of HCN1 through homologous recombination, demonstrating a key in vivo interaction between HCN1 and TRIP8b. TRIP8b dramatically alters the trafficking of HCN Channels heterologously expressed in Xenopus oocytes and human embryonic kidney 293 cells, causing a specific decrease in surface expression of HCN protein and Ih density, with a pronounced intracellular accumulation of HCN protein that is colocalized in discrete cytoplasmic clusters with TRIP8b. Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native Ih density. These data suggest a possible role for TRIP8b in regulating HCN Channel density in the plasma membrane.
Steven A Siegelbaum - One of the best experts on this subject based on the ideXlab platform.
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trip 8b ing up and down HCN Channel gating and trafficking
Biophysical Journal, 2014Co-Authors: Steven A Siegelbaum, Lei Hu, Bina SantoroAbstract:The proper neuronal functioning of ion Channels depends on their correct targeting to distinct polarized neuronal compartments, where the Channels often mediate highly specific functions. HCN1 Channels, which underlie the hyperpolarization-activated cation current (Ih) in many types of neurons, are targeted to the distal apical dendrites of hippocampal CA1 pyramidal neurons, where they regulate the integration of synaptic inputs and control excitability. Results from our laboratory and others indicate that the cytoplasmic protein TRIP8b is the major auxiliary subunit of HCN1 Channels in the brain, where it plays an important role in regulating HCN1 function, expression and localization. TRIP8b undergoes extensive alternative splicing at its N-terminus, with at least 10 splice variants detected in brain. All splice variants interact strongly with the C-terminus of all four HCN Channel isoforms (HCN1-4) at two different interaction surfaces. Whereas all TRIP8b isoforms inhibit Channel gating by antagonizing the normal action of cAMP to facilitate opening, the various isoforms have distinct effects on Channel trafficking. We identified two splice isoforms with opposing actions on HCN1 surface expression and distinct subcellular locales that are critical for HCN1 dendritic targeting. Our more recent results have identified the structural and functional bases for many of the regulatory actions of TRIP8b.
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Modulation of cyclic nucleotide-regulated HCN Channels by PIP 2 and receptors coupled to phospholipase C
Pflügers Archiv: European Journal of Physiology, 2007Co-Authors: Phillip Pian, Annalisa Bucchi, Anthony J. Decostanzo, Richard B. Robinson, Steven A SiegelbaumAbstract:Recent results indicate that phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), directly enhance the opening of hyperpolarization-activated, cyclic nucleotide-regulated (HCN) Channels by shifting their activation gating to more positive voltages. This contrasts with the action of phosphoinositides to inhibit the opening of the related cyclic nucleotide-gated (CNG) Channels involved in sensory signaling. We both review previous studies and present new experiments that investigate whether HCN Channels may be regulated by dynamic changes in PI(4,5)P2 levels caused by the receptor-mediated activation of phospholipase C (PLC). We coexpressed HCN1 or HCN2 Channels in Xenopus oocytes with the PLC-coupled bradykinin BK2 receptor, the muscarinic M1 receptor, or the TrkA receptor. Activation of all three receptors produced a positive shift in HCN Channel voltage gating, the opposite of the effect expected for PI(4,5)P2 depletion. This action was not caused by alterations in cAMP as the effect was preserved in HCN mutant Channels that fail to bind cAMP. The receptor effects were mediated by PLC activity, but did not depend on signaling through the downstream products of PI(4,5)P2 hydrolysis: IP3 or diacylglycerol (DAG). Importantly, the modulatory effects on gating were blocked by inhibitors of phosphatidylinositol (PI) kinases, suggesting a role for increased PI(4,5)P2 synthesis. Finally, we found that bradykinin exerted a similar PI kinase-dependent effect on the gating of native HCN Channels in cardiac sinoatrial node cells, suggesting that this pathway may represent a novel, physiologically relevant mechanism for enhancing HCN Channel function.
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regulation of HCN Channel surface expression by a novel c terminal protein protein interaction
The Journal of Neuroscience, 2004Co-Authors: Bina Santoro, Brian J Wainger, Steven A SiegelbaumAbstract:Hyperpolarization-activated cation currents (Ih) are carried by Channels encoded by a family of four genes (HCN1-4) that are differentially expressed within the brain in specific cellular and subcellular compartments. HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of Ih. Expression of Ih is also regulated by neuronal activity. To isolate proteins that may control HCN Channel expression or function, we performed yeast two-hybrid screens using the C-terminal cytoplasmic tails of the HCN proteins as bait. We identified a brain-specific protein, which has been previously termed TRIP8b (for TPR-containing Rab8b interacting protein) and PEX5Rp (for Pex5p-related protein), that specifically interacts with all four HCN Channels through a conserved sequence in their C-terminal tails. In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons. The dendritic expression of TRIP8b in layer V pyramidal neurons is disrupted after deletion of HCN1 through homologous recombination, demonstrating a key in vivo interaction between HCN1 and TRIP8b. TRIP8b dramatically alters the trafficking of HCN Channels heterologously expressed in Xenopus oocytes and human embryonic kidney 293 cells, causing a specific decrease in surface expression of HCN protein and Ih density, with a pronounced intracellular accumulation of HCN protein that is colocalized in discrete cytoplasmic clusters with TRIP8b. Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native Ih density. These data suggest a possible role for TRIP8b in regulating HCN Channel density in the plasma membrane.
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regulation of hyperpolarization activated HCN Channel gating and camp modulation due to interactions of cooh terminus and core transmembrane regions
The Journal of General Physiology, 2001Co-Authors: Jing W Wang, Shan Chen, Steven A SiegelbaumAbstract:Members of the hyperpolarization-activated cation (HCN) Channel family generate HCN currents (Ih) that are directly regulated by cAMP and contribute to pacemaking activity in heart and brain. The four different HCN isoforms show distinct biophysical properties. In cell-free patches from Xenopus oocytes, the steady-state activation curve of HCN2 Channels is 20 mV more hyperpolarized compared with HCN1. Whereas the binding of cAMP to a COOH-terminal cyclic nucleotide binding domain (CNBD) markedly shifts the activation curve of HCN2 by 17 mV to more positive potentials, the response of HCN1 is much less pronounced (4 mV shift). A previous deletion mutant study suggested that the CNBD inhibits hyperpolarization-gating in the absence of cAMP; the binding of cAMP shifts gating to more positive voltages by relieving this inhibition. The differences in basal gating and cAMP responsiveness between HCN1 and HCN2 were proposed to result from a greater inhibitory effect of the CNBD in HCN2 compared with HCN1. Here, we use a series of chimeras between HCN1 and HCN2, in which we exchange the NH2 terminus, the transmembrane domain, or distinct domains of the COOH terminus, to investigate further the molecular bases for the modulatory action of cAMP and for the differences in the functional properties of the two Channels. Differences in cAMP regulation between HCN1 and HCN2 are localized to sequence differences within the COOH terminus of the two Channels. Surprisingly, exchange of the CNBDs between HCN1 and HCN2 has little effect on basal gating and has only a modest one on cAMP modulation. Rather, differences in cAMP modulation depend on the interaction between the CNBD and the C-linker, a conserved 80–amino acid region that connects the last (S6) transmembrane segment to the CNBD. Differences in basal gating depend on both the core transmembrane domain and the COOH terminus. These data, taken in the context of the previous data on deletion mutants, suggest that the inhibitory effect of the CNBD on basal gating depends on its interactions with both the C-linker and core transmembrane domain of the Channel. The extent to which cAMP binding is able to relieve this inhibition is dependent on the interaction between the C-linker and the CNBD.
Alan S. Lewis - One of the best experts on this subject based on the ideXlab platform.
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HCN Channelopathy in external globus pallidus neurons in models of Parkinson's disease
Nature Neuroscience, 2011Co-Authors: C Savio Chan, Alan S. Lewis, Ryuichi Shigemoto, Kelly E Glajch, Tracy S Gertler, Jaime N Guzman, Jeff N Mercer, Alan B Goldberg, Tatiana Tkatch, Sheila M FlemingAbstract:Using a rat model of PD, the authors find a progressive decline in autonomous globus pallidus pacemaking. This loss was reversed by viral expression of the HCN Channel. However, the motor disability induced by DA depletion was not reversed, suggesting that the loss of pacemaking was a consequence, not a cause, of key network pathophysiology. Parkinson's disease is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined for the generation of pacemaking. After the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking, which normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion Channel that is essential in pacemaking, the hyperpolarization and cyclic nucleotide–gated (HCN) Channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, rather than a cause, of key network pathophysiology, a conclusion that is consistent with the ability of L-type Channel antagonists to attenuate silencing after DA depletion.
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the fast and slow ups and downs of HCN Channel regulation
Channels, 2010Co-Authors: Alan S. Lewis, Chad M. Estep, Dane M. ChetkovichAbstract:Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels (h Channels) form the molecular basis for the hyperpolarization-activated current, Ih, and modulation of h Channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h Channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, Channel conductance or subunit composition of h Channels. Here we provide a focused review examining mechanisms of h Channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in Ih in different biological models, as well as for molecular biologists to delineate the predicted h Channel changes associated with complex regulatory mechanisms in bo...
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The fast and slow ups and downs of HCN Channel regulation
Channels, 2010Co-Authors: Alan S. Lewis, Chad M. Estep, Dane M. ChetkovichAbstract:Hyperpolarization-activated cyclic nucleotide-gated (HCN) Channels (h Channels) form the molecular basis for the hyperpolarization-activated current, I(h), and modulation of h Channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h Channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, Channel conductance or subunit composition of h Channels. Here we provide a focused review examining mechanisms of h Channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in I(h) in different biological models, as well as for molecular biologists to delineate the predicted h Channel changes associated with complex regulatory mechanisms in both normal function and in disease states.
John J Hablitz - One of the best experts on this subject based on the ideXlab platform.
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developmental changes in HCN Channel modulation of neocortical layer 1 interneurons
Frontiers in Cellular Neuroscience, 2018Co-Authors: Andrew S Bohannon, John J HablitzAbstract:Layer (L1) interneurons (INs) play a key role in modulating the integration of inputs to pyramidal cells (PCs) and controlling cortical network activity. Hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) Channels are known to alter the intrinsic and synaptic excitability of PCs as well as select populations of GABAergic INs. However, the developmental profile and functional role of HCN Channels in diverse L1 IN populations is not completely understood. In the present study, we used electrophysiological characterization, in conjunction with unbiased hierarchical cluster analysis, to examine developmental modulation of L1 INs by HCN Channels in the rat medial agranular cortex (AGm). We identified three physiologically discrete IN populations which were classified as regular spiking (RS), burst accommodating (BA) and non-accommodating (NA). A distinct developmental pattern of excitability modulation by HCN Channels was observed for each group. RS and NA cells displayed distinct morphologies with modulation of EPSPs increasing in RS cells and decreasing in NA cells across development. The results indicate a possible role of HCN Channels in the formation and maintenance of cortical circuits through alteration of the excitability of distinct AGm L1 INs.
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HCN Channel modulation of synaptic integration in gabaergic interneurons in malformed rat neocortex
Frontiers in Cellular Neuroscience, 2017Co-Authors: Asher J Albertson, Andrew S Bohannon, John J HablitzAbstract:Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) Channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN Channels and Ih current amplitudes are reduced in layer (L) 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with increased EPSP temporal summation. Here, we examine the effects of HCN Channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN Channels antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN Channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN Channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN Channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.
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Regulation of epileptiform discharges in rat neocortex by HCN Channels
Journal of Neurophysiology, 2013Co-Authors: Asher J Albertson, Sidney B. Williams, John J HablitzAbstract:Hyperpolarization-activated, cyclic nucleotide-gated, nonspecific cation (HCN) Channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these Channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given the altered HCN Channel expression in epilepsy. We hypothesized that inhibition of HCN Channels would enhance bicuculline-induced epileptiform discharges. Whole cell recordings were obtained from layer (L)2/3 and L5 pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 μM), HCN Channel inhibition with ZD 7288 (20 μM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN Channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN Channel inhibiti...
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abnormal pyramidal cell morphology and HCN Channel expression in cortical dysplasia
Epilepsia, 2010Co-Authors: John J Hablitz, Jianming YangAbstract:Cortical dysplasia is often associated with intractable seizures. Studies in animal models have described changes in inhibitory and excitatory synaptic function that contribute to hyperexcitability. The role of changes in intrinsic excitability and abnormal dendritic properties has received less attention. Changes in hyperpolarization-activated non-selective cation (HCN) Channels have been implicated in several models of epilepsy. Here we review evidence for alterations in HCN Channels and dendritic morphology in the rat freeze-lesion model of cortical dysplasia. Immunocytochemical HCN1 staining, typically seen in the apical dendrites of layer V pyramidal cells in normal cortex, was greatly reduced in the region adjacent to the freeze-induced microgyrus. Although staining was preserved in layer I, fewer dendrites were stained in upper cortical layers. Deeper cortical layers were virtually devoid of immunoreactivity. Examination of biocytin-labeled pyramidal cells revealed markedly altered dendritic trees in the lesioned animals. In addition, resting membrane properties were altered and a subpopulation of neurons with abnormal dendritic arbors was present. These changes are likely to interact with the previously reported synaptic changes in this model of cortical dysplasia. HCN Channel alterations are a potentially important cellular mechanism underlying hyperexcitability in cortical dysplasia.
