Genomes and Genes
n type calcium channels
Summary: CALCIUM CHANNELS that are concentrated in neural tissue. Omega toxins inhibit the actions of these channels by altering their voltage dependence.
- Gamper N, Reznikov V, Yamada Y, Yang J, Shapiro M. Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J Neurosci. 2004;24:10980-92 pubmed..We suggest that differential use of PIP2 signals underlies specificity of Gq/11-coupled receptor actions on the channels ..
- Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg A, Pietrobon D. Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. J Biol Chem. 2005;280:17678-86 pubmed
- Agler H, Evans J, Tay L, Anderson M, Colecraft H, Yue D. G protein-gated inhibitory module of N-type (ca(v)2.2) ca2+ channels. Neuron. 2005;46:891-904 pubmed..Thus, an NT module, acting via interactions with the I-II loop, appears fundamental to such modulation. ..
- Khanna R, Sun L, Li Q, Guo L, Stanley E. Long splice variant N type calcium channels are clustered at presynaptic transmitter release sites without modular adaptor proteins. Neuroscience. 2006;138:1115-25 pubmed..2 argues against the idea that these modular adaptor proteins anchor CaV2.2 at presynaptic nerve terminals. ..
- Heneghan J, Mitra Ganguli T, Stanish L, Liu L, Zhao R, Rittenhouse A. The Ca2+ channel beta subunit determines whether stimulation of Gq-coupled receptors enhances or inhibits N current. J Gen Physiol. 2009;134:369-84 pubmed publisher..Moreover, these findings predict that at synapses, modulation of N-channel activity by M(1)Rs or NK-1Rs will fluctuate between enhancement and inhibition based on the presence of palmitoylated Ca(V)beta2a. ..
- Mezghrani A, Monteil A, Watschinger K, Sinnegger Brauns M, Barrere C, Bourinet E, et al. A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels. J Neurosci. 2008;28:4501-11 pubmed publisher..We conclude that this destructive interaction mechanism promoted by Ca(v) mutants is likely to occur in EA2 and in other inherited dominant channelopathies. ..
- Takahashi E, Ito M, Miyamoto N, Nagasu T, Ino M, Tanaka I. Increased glucose tolerance in N-type Ca2+ channel alpha(1B)-subunit gene-deficient mice. Int J Mol Med. 2005;15:937-44 pubmed..Thus, N-type Ca2+ channel blockers might be candidate anti-diabetic/anti-obesity agents. ..
- Guo J, Ikeda S. Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. Mol Pharmacol. 2004;65:665-74 pubmed..These results suggest a mechanism by which endocannibinoids might influence presynaptic function. ..
- Liu L, Roberts M, Rittenhouse A. Phospholipid metabolism is required for M1 muscarinic inhibition of N-type calcium current in sympathetic neurons. Eur Biophys J. 2004;33:255-64 pubmed..In contrast to AA, applying LPA did not inhibit whole cell currents. Taken together, these findings suggest that the slow pathway requires M1Rs, Gqalpha, PLC, PIP2, PLA2, and AA for N-current inhibition. ..
- Fellin T, Luvisetto S, Spagnolo M, Pietrobon D. Modal gating of human CaV2.1 (P/Q-type) calcium channels: II. the b mode and reversible uncoupling of inactivation. J Gen Physiol. 2004;124:463-74 pubmed..1 channels could be a potent and versatile mechanism for the modulation of synaptic strength and plasticity as well as of neuronal excitability and other postsynaptic Ca2+-dependent processes. ..
- Altier C, Dale C, Kisilevsky A, Chapman K, Castiglioni A, Matthews E, et al. Differential role of N-type calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363-73 pubmed..In contrast, both N-type channel isoforms (e37a- and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain. ..
- Liu L, Heneghan J, Michael G, Stanish L, Egertová M, Rittenhouse A. L- and N-current but not M-current inhibition by M1 muscarinic receptors requires DAG lipase activity. J Cell Physiol. 2008;216:91-100 pubmed publisher..These results extend our previous findings that the signaling pathway mediating L- and N-current inhibition diverges from the pathway initiating M-current inhibition. ..
- Castiglioni A, Raingo J, Lipscombe D. Alternative splicing in the C-terminus of CaV2.2 controls expression and gating of N-type calcium channels. J Physiol. 2006;576:119-34 pubmed..Our studies of the e37a/e37b splice site reveal a multifunctional domain in the C-terminus of Ca(V)2.2 that regulates the overall activity of N-type calcium channels in nociceptors. ..
- Tedford H, Zamponi G. Direct G protein modulation of Cav2 calcium channels. Pharmacol Rev. 2006;58:837-62 pubmed..Twenty-five years after this mode of physiological regulation was first described, we review the investigations that have led to our current understanding of its molecular mechanisms. ..
- Chaudhuri D, Issa J, Yue D. Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels. J Gen Physiol. 2007;129:385-401 pubmed..This enhanced-opening mechanism suggests that the CDF evoked during action-potential trains would produce not only larger, but longer-lasting Ca(2+) responses, an outcome with potential ramifications for short-term synaptic plasticity. ..
- Zhen X, Xie C, Fitzmaurice A, Schoonover C, Orenstein E, Yang J. Functional architecture of the inner pore of a voltage-gated Ca2+ channel. J Gen Physiol. 2005;126:193-204 pubmed..This work provides an impetus for future studies on ion permeation, gating, and drug binding of VGCCs. ..
- Mitra Ganguli T, Vitko I, Perez Reyes E, Rittenhouse A. Orientation of palmitoylated CaVbeta2a relative to CaV2.2 is critical for slow pathway modulation of N-type Ca2+ current by tachykinin receptor activation. J Gen Physiol. 2009;134:385-96 pubmed publisher..These findings support our previous hypothesis that Ca(V)beta2a's palmitoyl groups directly interact with an inhibitory site on Ca(V)2.2 to block N-current inhibition by SP. ..
- Mich P, Horne W. Alternative splicing of the Ca2+ channel beta4 subunit confers specificity for gabapentin inhibition of Cav2.1 trafficking. Mol Pharmacol. 2008;74:904-12 pubmed publisher..This mechanism may help to explain why gabapentin is both effective and selective in the treatment of neuropathic pain states that involve up-regulation of alpha2delta subunits. ..
- Tsunemi T, Ishikawa K, Jin H, Mizusawa H. Cell-type-specific alternative splicing in spinocerebellar ataxia type 6. Neurosci Lett. 2008;447:78-81 pubmed publisher..Our results suggest that toxic isoform mRNA is increased in a Purkinje cell-specific manner, which may result in SCA6-associated selective neurodegeneration. ..
- Luvisetto S, Fellin T, Spagnolo M, Hivert B, Brust P, Harpold M, et al. Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits. J Gen Physiol. 2004;124:445-61 pubmed
- Adams P, Garcia E, David L, Mulatz K, Spacey S, Snutch T. Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies. Channels (Austin). 2009;3:110-21 pubmed..Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies. ..
- Raingo J, Castiglioni A, Lipscombe D. Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci. 2007;10:285-92 pubmed..Our data define the molecular origins of voltage-independent inhibition of N-type channels in the pain pathway. ..
- Bell T, Thaler C, Castiglioni A, Helton T, Lipscombe D. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron. 2004;41:127-38 pubmed..8. Cell-specific inclusion of exon 37a correlates closely with significantly larger N-type currents in nociceptive neurons. This unique splice isoform of the N-type channel could represent a novel target for pain management. ..
- Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S, et al. Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci. 2007;34:261-70 pubmed..Therefore, our results do not support the notion that the alteration of the channel properties may underlie the pathogenic mechanism of SCA6. ..
- Lin Y, McDonough S, Lipscombe D. Alternative splicing in the voltage-sensing region of N-Type CaV2.2 channels modulates channel kinetics. J Neurophysiol. 2004;92:2820-30 pubmed..Our results suggest that alternative splicing in the S3-S4 linker influences the kinetics but not the voltage dependence of N-type channel gating. ..
- Watase K, Barrett C, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, et al. Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci U S A. 2008;105:11987-92 pubmed publisher..The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant Ca(V)2.1 channels. ..
- Vitko I, Shcheglovitov A, Baumgart J, Arias Olguin I, Murbartián J, Arias J, et al. Orientation of the calcium channel beta relative to the alpha(1)2.2 subunit is critical for its regulation of channel activity. PLoS ONE. 2008;3:e3560 pubmed publisher..These results show that the orientation of the Ca(v)beta subunit relative to the alpha(1)2.2 subunit is critical, and suggests additional points of contact between these subunits are required for Ca(v)beta to regulate channel activity. ..
- Xie C, Zhen X, Yang J. Localization of the activation gate of a voltage-gated Ca2+ channel. J Gen Physiol. 2005;126:205-12 pubmed..Our results suggest that the S6 helices of the alpha1 subunit of VGCCs undergo conformation changes during gating and the activation gate is located at the intracellular end of the pore. ..
- Leroy J, Richards M, Richards M, Butcher A, Nieto Rostro M, Pratt W, et al. Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties. J Neurosci. 2005;25:6984-96 pubmed
- Lee A, Zhou H, Scheuer T, Catterall W. Molecular determinants of Ca(2+)/calmodulin-dependent regulation of Ca(v)2.1 channels. Proc Natl Acad Sci U S A. 2003;100:16059-64 pubmed..This multifaceted mechanism allows positive regulation of Cav2.1 in response to local Ca2+ increases (CDF) and negative regulation during more global Ca2+ increases (CDI). ..
- Kinoshita M, Nukada T, Asano T, Mori Y, Akaike A, Satoh M, et al. Binding of G alpha(o) N terminus is responsible for the voltage-resistant inhibition of alpha(1A) (P/Q-type, Ca(v)2.1) Ca(2+) channels. J Biol Chem. 2001;276:28731-8 pubmed..These findings demonstrate that the voltage-resistant inhibition of the P/Q-type, alpha(1A) channel is caused by the interaction between the C-terminal domain of Ca(2+) channel alpha(1A) subunit and the N-terminal region of G alpha(o). ..
- Wappl E, Koschak A, Poteser M, Sinnegger M, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem. 2002;277:6960-6 pubmed..In contrast to other EA-2 mutations, AY1593/1594D and G293R form at least partially functional channels. ..
- Saegusa H, Matsuda Y, Tanabe T. Effects of ablation of N- and R-type Ca(2+) channels on pain transmission. Neurosci Res. 2002;43:1-7 pubmed..3-/- mice, was also observed in the Ca(v)2.2-/- mice. Therefore, it is suggested that these mutant mice could provide novel models to delineate the nociceptive and antinociceptive mechanisms. ..
- Zhang Y, Mori M, Burgess D, Noebels J. Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci. 2002;22:6362-71 pubmed..These alterations increase the probability for abnormal thalamocortical synchronization and absence epilepsy in tg, lh, and stg mice. ..
- Soong T, DeMaria C, Alvania R, Zweifel L, Liang M, Mittman S, et al. Systematic identification of splice variants in human P/Q-type channel alpha1(2.1) subunits: implications for current density and Ca2+-dependent inactivation. J Neurosci. 2002;22:10142-52 pubmed..These findings significantly expand the anticipated scope of functional diversity produced by splice variation of P/Q-type channels. ..
- Liu L, Rittenhouse A. Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons. Proc Natl Acad Sci U S A. 2003;100:295-300 pubmed..Our finding that AA participates in the slow pathway strongly suggests that it may be the previously unknown diffusible second messenger. ..
- Kitano J, Nishida M, Itsukaichi Y, Minami I, Ogawa M, Hirano T, et al. Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel. J Biol Chem. 2003;278:25101-8 pubmed..These data suggest that the assembly of mGluR1 and Cav2.1 provides the mechanism that ensures spatiotemporal regulation of [Ca2+]i in glutamatergic neurotransmission. ..
- Liu L, Gonzalez P, Barrett C, Rittenhouse A. The calcium channel ligand FPL 64176 enhances L-type but inhibits N-type neuronal calcium currents. Neuropharmacology. 2003;45:281-92 pubmed
- Liang H, DeMaria C, Erickson M, Mori M, Alseikhan B, Yue D. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family. Neuron. 2003;39:951-60 pubmed
- Stotz S, Barr W, McRory J, Chen L, Jarvis S, Zamponi G. Several structural domains contribute to the regulation of N-type calcium channel inactivation by the beta 3 subunit. J Biol Chem. 2004;279:3793-800 pubmed..2 did not alter the regulation of the channel by wild type and chimeric beta subunits. Hence, the molecular underpinnings of beta subunit regulation of voltage-gated calcium channels appear to vary with calcium channel subtype. ..
- Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J. 2001;20:2349-56 pubmed..This finding clearly demonstrates that the N-type VDCC is essential for development of neuropathic pain and, therefore, controlling the activity of this channel can be of great importance for the management of neuropathic pain. ..
- Qian J, Noebels J. Presynaptic Ca2+ channels and neurotransmitter release at the terminal of a mouse cortical neuron. J Neurosci. 2001;21:3721-8 pubmed
- Liu L, Barrett C, Rittenhouse A. Arachidonic acid both inhibits and enhances whole cell calcium currents in rat sympathetic neurons. Am J Physiol Cell Physiol. 2001;280:C1293-305 pubmed..AA also enhanced the rate of N-type current activation. These findings indicate that AA causes multiple changes in sympathetic Ca(2+) currents. ..
- Currie K, Fox A. Differential facilitation of N- and P/Q-type calcium channels during trains of action potential-like waveforms. J Physiol. 2002;539:419-31 pubmed..Since the ratio of N-type to P/Q-type Ca(2+) channels varies widely between synapses, differential facilitation may contribute to the fine tuning of synaptic transmission, thereby increasing the computational repertoire of neurons. ..
- Sharp A, Black J, Dubel S, Sundarraj S, Shen J, Yunker A, et al. Biochemical and anatomical evidence for specialized voltage-dependent calcium channel gamma isoform expression in the epileptic and ataxic mouse, stargazer. Neuroscience. 2001;105:599-617 pubmed
- Raghib A, Bertaso F, Davies A, Page K, Meir A, Bogdanov Y, et al. Dominant-negative synthesis suppression of voltage-gated calcium channel Cav2.2 induced by truncated constructs. J Neurosci. 2001;21:8495-504 pubmed..Our results indicate that the mechanism of suppression of Ca(v)2.2 by truncated constructs containing domain I involves inhibition of channel synthesis, which may represent a role of endogenously expressed truncated Ca(v) isoforms. ..
- Frontali M. Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder?. Brain Res Bull. 2001;56:227-31 pubmed..In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders. ..
- Tsunemi T, Saegusa H, Ishikawa K, Nagayama S, Murakoshi T, Mizusawa H, et al. Novel Cav2.1 splice variants isolated from Purkinje cells do not generate P-type Ca2+ current. J Biol Chem. 2002;277:7214-21 pubmed..These results suggest that P-type-specific splice variants may exist but that post-translational processing or modification by uncharacterized interacting proteins is also required for generating the P-type current. ..
- Moss F, Viard P, Davies A, Bertaso F, Page K, Graham A, et al. The novel product of a five-exon stargazin-related gene abolishes Ca(V)2.2 calcium channel expression. EMBO J. 2002;21:1514-23 pubmed
- Helton T, Kojetin D, Cavanagh J, Horne W. Alternative splicing of a beta4 subunit proline-rich motif regulates voltage-dependent gating and toxin block of Cav2.1 Ca2+ channels. J Neurosci. 2002;22:9331-9 pubmed..These results raise interesting questions about the functional role that alternative splicing of the beta4 subunit has played in the evolution of complex neural networks. ..
- Geib S, Sandoz G, Cornet V, Mabrouk K, Fund Saunier O, Bichet D, et al. The interaction between the I-II loop and the III-IV loop of Cav2.1 contributes to voltage-dependent inactivation in a beta -dependent manner. J Biol Chem. 2002;277:10003-13 pubmed..These data provide novel insights into the mechanisms whereby the beta subunit, the I-II loop, and the III-IV loop altogether can contribute to regulate inactivation in high voltage-activated calcium channels. ..
- Colecraft H, Brody D, Yue D. G-protein inhibition of N- and P/Q-type calcium channels: distinctive elementary mechanisms and their functional impact. J Neurosci. 2001;21:1137-47 pubmed..Variable expression of N- and P/Q-type channels at spatially distinct synapses therefore offers the potential for custom regulation of both synaptic efficacy and synchrony, by G-protein inhibition. ..