T-Type Calcium Channel

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Ae Nim Pae - One of the best experts on this subject based on the ideXlab platform.

Miguel Martin-caraballo - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of T-Type Calcium Channel expression by sodium butyrate in prostate cancer cells.
    European journal of pharmacology, 2014
    Co-Authors: Erika M. Weaver, Jennifer L. Hearne, Francis J. Zamora, Yvonne A. Puplampu-dove, Ezechielle Kiessu, Miguel Martin-caraballo

    Abstract Several cellular mechanisms contribute to the neuroendocrine differentiation of prostate cancer cells, including exposure to sodium butyrate (NaBu), a naturally occurring salt of the short chain fatty acid n-butyric acid. NaBu belongs to a class of histone deacetylase inhibitors with potential anticancer function. T-Type Calcium Channel expression constitutes an important route for Calcium influx in tumor cells that may trigger changes in cell proliferation and differentiation. In this work we investigated the role NaBu on the differentiation of lymph node carcinoma of the prostate (LNCaP) cells and its effect on T-Type Ca 2+ Channel expression. NaBu stimulates the morphological and molecular differentiation of LNCaP cells. Stimulation of LNCaP cells with NaBu evokes a significant increase in the expression of the Ca v 3.2 T-Type Channel subunits. Furthermore, the increased Ca v 3.2 expression promotes membrane insertion of T-Type Ca 2+ Channels capable of generating fast inactivating Ca 2+ currents, sensitive to 100 μM Ni 2+ ions. Inhibition of T-Type Ca 2+ Channel function reduces the outgrowth of neurite-like processes in LNCaP cells. NaBu-evoked expression of T-Type Ca 2+ Channels is also involved in the regulation of cell viability. Inhibition of T-Type Ca 2+ Channels causes a significant reduction in the viability of LNCaP cells treated with 1 mM NaBu, suggesting that Ca 2+ influx via T-Type Channels can promote cell proliferation. However, increased expression of T-Type Ca 2+ Channels enhanced the cytotoxic effect of thapsigargin and paclitaxel on cell proliferation. These findings demonstrate that NaBu stimulates T-Type Ca 2+ Channel expression, thereby regulating both the morphological differentiation and growth of prostate cancer cells.

  • Abstract 2119: Regulation of T-Type Calcium Channel expression during IL-6 induced neuroendocrine differentiation of prostate cancer cells
    Endocrinology, 2014
    Co-Authors: Erika M. Weaver, Jennifer L. Hearne, Miguel Martin-caraballo

    Prostate cancer is the most common cancer among men. At early stages, the growth of prostate cancers is androgen dependent and therefore therapies designed to reduce the androgen concentration/receptor activation are effective in promoting tumor regression. At later stages, however, the growth of prostate cancers becomes androgen independent, leading to increased mortality. The switch to an androgen-refractory state is associated with neuroendocrine differentiation of prostate cancer cells. Several factors including interleukin-6 (IL-6) and increased cAMP production promote neuroendocrine differentiation of prostate cancer cells. How these factors promote neuroendocrine differentiation is not completely understood. In this work we investigated whether IL-6 evoked neuroendocrine differentiation of prostate cancer cells results in the stimulation of T-Type Calcium Channel expression in the prostate cancer cell line LNCaP. Treatment of LNCaP cells with IL-6 for four days evokes considerable morphological and molecular changes consistent with neuroendocrine differentiation, including the presence of rounded cell bodies, the appearance of long dendritic-like processes and the expression of chromogranin-A. IL-6 evoked neuroendocrine differentiation of LNCaP cells results in a 3-fold increase in the protein expression of the T-Type Calcium Channel subunit Cav3.2. Transcripts for the Cav3.2 but not Cav3.1 or Cav3.3 subunits can be detected in IL-6-treated LNCaP cells. Real time PCR analysis indicates no change in Cav3.2 mRNA expression between control (non-stimulated) and IL-6 stimulated LNCaP cells, suggesting that T-Type Calcium Channel expression is regulated by a post-transcriptional mechanism. Electrophysiological recordings reveal that increased Cav3.2 protein expression following IL-6 stimulation of LNCaP cells does not result in increased expression of functional Channels in the membrane. Functional expression of Cav3.2 Channels is facilitated by stimulation of LNCaP cells with forskolin an agent that increases intracellular cAMP. These results indicate that changes in T-Type Calcium Channel expression and intracellular Calcium during neuroendocrine differentiation of LNCaP cells are regulated by the interplay of multiple factors. Thus, it appears that T-Type Calcium Channels could be a target for future therapeutic strategies against prostate cancers refractory to anti-androgen therapies. Citation Format: Erika Weaver, Jennifer L. Hearne, Miguel Martin-Caraballo. Regulation of T-Type Calcium Channel expression during IL-6 induced neuroendocrine differentiation of prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2119. doi:10.1158/1538-7445.AM2014-2119

Jae Yeol Lee - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis and biological evaluation of pyrrolidine-based T-Type Calcium Channel inhibitors for the treatment of neuropathic pain
    Journal of enzyme inhibition and medicinal chemistry, 2018
    Co-Authors: Hak Kyun Yang, Jae Yeol Lee, Kyu-sung Jeong, Woo Seung Son, Sang Min Lim, Keon Seung Lim, Gun Hee Kim, Eun Jeong Lim, Changdev G. Gadhe, Ae Nim Pae

    The treatment of neuropathic pain is one of the urgent unmet medical needs and T-Type Calcium Channels are promising therapeutic targets for neuropathic pain. Several potent T-Type Channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-Type Calcium Channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav3.1 and Cav3.2 Channel inhibitory activities. Among potent inhibitors against both Cav3.1 and Cav3.2 Channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-Type Calcium Channels can be a promising therapeutic strategy for the treatment of neuropathic pain.

  • T-Type Calcium Channel antagonists suppress tremor in two mouse models of essential tremor.
    Neuropharmacology, 2010
    Co-Authors: Adrian Handforth, Jae Yeol Lee, Gregg E. Homanics, Douglas F. Covey, Kathiresan Krishnan, Kenji Sakimura, Fredricka C. Martin, Arnulfo Quesada

    Essential tremor is a common disorder that lacks molecular targets for therapeutic development. T-Type Calcium Channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in essential tremor. We therefore tested whether compounds that antagonize T-Type Calcium Channel currents suppress tremor in two mouse models that possess an essential tremor-like pharmacological response profile. Tremor was measured using digitized spectral motion power analysis with harmaline-induced tremor and in the GABA(A) receptor α1 subunit-null model. Mice were given ethosuximide, zonisamide, the neuroactive steroid (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), the 3,4-dihydroquinazoline derivative KYS05064, the mibefradil derivative NNC 55-0396, or vehicle. In non-sedating doses, each compound reduced harmaline-induced tremor by at least 50% (range of maximal suppression: 53-81%), and in the GABA(A) α1-null model by at least 70% (range 70-93%). Because the T-Type Calcium Channel Cav3.1 is the dominant subtype expressed in the inferior olive, we assessed the tremor response of Cav3.1-deficient mice to harmaline, and found that null and heterozygote mice exhibit as much tremor as wild-type mice. In addition, ECN and NNC 55-0396 suppressed harmaline tremor as well in Cav3.1-null mice as in wild-type mice. The finding that five T-Type Calcium antagonists suppress tremor in two animal tremor models suggests that T-Type Calcium Channels may be an appropriate target for essential tremor therapy development. It is uncertain whether medications developed to block only the Cav3.1 subtype would exhibit efficacy.

  • discovery of potent t type Calcium Channel blocker
    Bioorganic & Medicinal Chemistry Letters, 2007
    Co-Authors: Han Na Seo, Hyewhon Rhim, Yoonjee Kim, Ja Youn Choi, Yun Jeong Choe, So Ha Lee, Jungahn Kim, Dong Jun Joo, Jae Yeol Lee

    The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC(50)=41+/-1 nM) against T-Type Calcium Channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.

  • Synthesis and biological evaluation of novel T-Type Calcium Channel blockers.
    Bioorganic & medicinal chemistry letters, 2006
    Co-Authors: Ja Youn Choi, Hyewhon Rhim, Ae Nim Pae, Han Na Seo, Min Joo Lee, Seong Jun Park, Sung Jun Park, Ji Young Jeon, Joo Hi Kang, Jae Yeol Lee

    Abstract 3,4-Dihydroquinazoline analogues substituted by N-methyl-N-(5-pyrrolidinopentyl)amine at the 2-position were synthesized and their blocking effects were evaluated for T- and N-type Calcium Channels. Compound 11b (KYS05080), compared to mibefradil (IC50 = 1.34 ± 0.49 μM), was about 5-fold potent (IC50 = 0.26 ± 0.01 μM) for T-Type Calcium Channel (α1G) blocking and its selectivity of T/N-type was also improved (7.5 versus 1.4 of mibefradil).

  • First pharmacophoric hypothesis for T-Type Calcium Channel blockers.
    Bioorganic & medicinal chemistry, 2004
    Co-Authors: Munikumar Reddy Doddareddy, Hun Yeong Koh, Yong Seo Cho, Hee Kyung Jung, Jae Yeol Lee, Yong Sup Lee, Ae Nim Pae

    A three-dimensional pharmacophore model was developed for T-Type Calcium Channel blockers in order to map common structural features of highly active compounds by using CATALYST program. In the absence of three dimensional structure based information like binding mode and unavailability of more number of specific T-Type Calcium Channel blockers, this hypothesis which consists of three hydrophobic regions, one hydrogen bond acceptor and one positive ionizable regions will act as a valuable tool in designing new ligands. Further more after the withdrawal of mibefradil, the first marketed T-Type Calcium Channel blocker, due to the drug-drug interactions, there is an urgent need for more work in this interest.

Matthias Holdhoff - One of the best experts on this subject based on the ideXlab platform.

  • timed sequential therapy of the selective t type Calcium Channel blocker mibefradil and temozolomide in patients with recurrent high grade gliomas
    Neuro-oncology, 2017
    Co-Authors: Matthias Holdhoff, Jeffrey G Supko, Louis B Nabors, Arati Desai, Tobias Walbert, Glenn J Lesser, William L Read, Frank S Lieberman, Martin A Lodge, Jeffrey Leal

    Background Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-Type Calcium Channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

  • nimg 35results of exploratory 18f flt pet imaging in ten recurrent high grade glioma patients treated with the selective t type Calcium Channel blocker mibefradil followed by temozolomide abtc trial 1101
    Neuro-oncology, 2015
    Co-Authors: Matthias Holdhoff, Arati Desai, Glenn J Lesser, Martin A Lodge, Asim K Bag, Burt L Nabors, Akiva Mintz, David A Mankoff, Frank S Lieberman

    BACKGROUND: Mibefradil (MIB) is a selective T-Type Calcium Channel blocker that has shown preclinical impact on cell cycle activity, specifically arrest at G1/S in tumor cells, suggesting a potential chemo-sensitizing effect if given prior to chemotherapy. In our study, MIB was administered orally QID x 7 days prior to standard temozolomide (150-200 mg/m2 x 5/28d) in recurrent high-grade glioma (HGG) patients. 18F-FLT PET was used as an exploratory imaging biomarker to assess influence of MIB on overall tracer accumulation in tumor. METHODS: 18F-FLT PET was performed in 10 patients treated at the maximum tolerated dose of MIB (87.5 mg po QID) at 5 different institutions. Prior to MIB administration, 2 PET scans were performed as a double baseline to assess repeatability of PET measurements. A third scan was performed on day 7 of MIB treatment to assess 18F-FLT uptake for response. Tumor standardized uptake values (SUVs) were measured at a central laboratory by automatically positioning a 1mL sphere at the region of highest uptake (SUVpeak). RESULTS: The double baseline data indicated 95% limits of repeatability of 18.5% (6.7% within-patient coefficient of variation) for SUVpeak. Two of the 10 patients demonstrated a drop in SUVpeak after 7 days of MIB that exceeded these limits (-47% and -67%). No significant change between double baseline and day 7 of MIB was seen in the remaining 8 patients. CONCLUSIONS: In this first 18F-FLT PET imaging study within a multicenter HGG trial, 18F-FLT PET was found to be feasible and highly repeatable. The results suggest influence of MIB on tumor accumulation of the radiotracer, possibly in part due to alterations in cell cycle activity in a subset of patients, but the precise mechanism remains to be determined as tracer delivery/transport effects may also be contributing to the decline in signal observed in the two patients.

Gerald W. Zamponi - One of the best experts on this subject based on the ideXlab platform.

  • Recent advances in the development of T‐type Calcium Channel blockers for pain intervention
    British journal of pharmacology, 2017
    Co-Authors: Terrance P. Snutch, Gerald W. Zamponi

    Cav3.2 T-Type Calcium Channels are important regulators of pain signals in afferent pain pathway, and their activities are dysregulated during various chronic pain states. Therefore it stands to reason that inhibiting T-Type Calcium Channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief. This is supported by early pharmacological studies with T-Type Channel blockers such as ethosuximide, and by analgesic effects of siRNA depletion of Cav3.2 Channels. In the past five years, considerable effort has been applied towards identifying novel classes of T-Type Calcium Channel blockers. Here we review recent developments in the discovery of novel classes of T-Type Calcium Channel blockers, and their analgesics effects in animal models of pain and in clinical trials.

  • Cooperative roles of glucose and asparagine-linked glycosylation in T-Type Calcium Channel expression
    Pflügers Archiv - European Journal of Physiology, 2016
    Co-Authors: Joanna Lazniewska, Yuriy Rzhepetskyy, Fang-xiong Zhang, Gerald W. Zamponi, Norbert Weiss

    T-Type Calcium Channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Enhanced T-Type Channel expression has been causally linked to a number of pathological conditions including peripheral painful diabetic neuropathy. Recently, it was demonstrated that asparagine-linked glycosylation not only plays an essential role in regulating cell surface expression of Ca_v3.2 Channels, but may also support glucose-dependent potentiation of T-Type currents. However, the underlying mechanisms by which N-glycosylation and glucose levels modulate the expression of T-Type Channels remain elusive. In the present study, we show that site-specific N-glycosylation of Ca_v3.2 is essential to stabilize expression of the Channel at the plasma membrane. In contrast, elevated external glucose concentration appears to potentiate intracellular forward trafficking of the Channel to the cell surface, resulting in an increased steady-state expression of the Channel protein at the plasma membrane. Collectively, our study indicates that glucose and N-glycosylation act in concert to control the expression of Ca_v3.2 Channels, and that alteration of these mechanisms may contribute to the altered expression of T-Type Channels in pathological conditions.

  • 1,4-Dihydropyridine derivatives with T-Type Calcium Channel blocking activity attenuate inflammatory and neuropathic pain
    Pflügers Archiv - European Journal of Physiology, 2015
    Co-Authors: Chris Bladen, Vinicius M. Gadotti, N. Daniel Berger, Miyase G. Gündüz, Rahime Şimşek, Cihat Şafak, Gerald W. Zamponi

    We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-Type over L-type Calcium Channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-Type Channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Ca_v3.2 over Ca_v1.2 L-type Channels. The effects of the two lead compounds, termed N10 and N12, on Ca_v3.2 Channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Ca_v3.2 null mice. Altogether, our data reveal a novel class of T-Type Channel blocking DHPs for potential pain therapies.

  • Characterization of novel cannabinoid based T-Type Calcium Channel blockers with analgesic effects
    ACS chemical neuroscience, 2014
    Co-Authors: Chris Bladen, Steven W. Mcdaniel, Vinicius M. Gadotti, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi

    Low-voltage-activated (T-Type) Calcium Channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these Channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-Type Channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-Type Calcium Channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure–activity relationship and optimization studies have led to the discovery of a new T-Type Calcium Channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse mod...

  • expression of t type Calcium Channel splice variants in human glioma
    Glia, 2004
    Co-Authors: Isabelle Latour, Deon F Louw, Aaron M Beedle, Jawed Hamid, Garnette R Sutherland, Gerald W. Zamponi

    In humans, three isoforms of the T-Type (Ca(v)3.1) Calcium-Channel alpha(1) subunit have been reported as a result of alternate splicing of exons 25 and 26 in the III-IV linker region (Ca(v)3.1a, Ca(v)3.1b or Ca(v)3.1bc). In the present study, we report that human glioma express Ca(v)3.1 Channels in situ, that splicing of these exons is uniquely regulated and that there is expression of a glioma-specific novel T-Type variant (Ca(v)3.1ac). Seven human glioma samples were collected at surgery, RNA was extracted, and cDNA was produced for RT-PCR analysis. In addition, three glioma cell lines (U87, U563, and U251N), primary cultures of human fetal astrocytes, as well as adult and fetal human brain cDNA were used. Previously described Ca(v)3.1 splice variants were present in glioma samples, cultured cells and whole brain. Consistent with the literature, our results reveal that in the normal adult brain, Ca(v)3.1a transcripts predominate, while Ca(v)3.1b is mostly fetal-specific. RT-PCR results on glioma and glioma cell lines showed that Ca(v)3.1 expression in tumor cells resemble fetal brain expression pattern as Ca(v)3.1bc is predominantly expressed. In addition, we identified a novel splice variant, Ca(v)3.1ac, expressed in three glioma biopsies and one glioma cell line, but not in normal brain or fetal astrocytes. Transient expression of this variant demonstrates that Ca(v)3.1ac displays similar current-voltage and steady-state inactivation properties compared with Ca(v)3.1b, but a slower recovery from inactivation. Taken together, our data suggest glioma-specific Ca(v)3.1 gene regulation, which could possibly contribute to tumor pathogenesis.