Voltage-gated calcium channels in chronic pain: emerging role of alternative splicing

N- and T-type voltage-gated calcium channels are key established players in chronic pain. Current work suggests that alternative splicing of these channels constitutes an important aspect in the investigation of their roles in the pathogenesis of chronic pain. Recent N-type channel studies describe a nociceptor-enriched alternatively spliced module responsible for voltage-independent G protein modulation and internalization, which is implicated in the control of distinct nociceptive pathways. On the contrary, although a large body of work has demonstrated that peripheral Cav3.2-encoded T-type currents are involved in several types of chronic pain, little is known with respect to the expression of numerous newly discovered splice variants in specific pain pathways. The elucidation of the new layers of molecular complexity uncovered in N- and T-type channel splice variants and their respective locations and roles in different pain pathways will allow for the development of better therapeutic strategies for the treatment of chronic pain.

[1]  Hiroshi Ikeda,et al.  Synaptic Plasticity in Spinal Lamina I Projection Neurons That Mediate Hyperalgesia , 2003, Science.

[2]  J. Hell,et al.  Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  Q. Hogan,et al.  Contribution of Calcium Channel Subtypes to the Intracellular Calcium Signal in Sensory Neurons: The Effect of Injury , 2007, Anesthesiology.

[4]  A. J. Castiglioni,et al.  Cell-Specific Alternative Splicing Increases Calcium Channel Current Density in the Pain Pathway , 2004, Neuron.

[5]  J. McGivern.  Targeting N-type and T-type calcium channels for the treatment of pain. , 2006, Drug discovery today.

[6]  J. Jordan,et al.  Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel , 2000, Nature.

[7]  G. Milligan,et al.  G‐proteins and G‐protein subunits mediating cholinergic inhibition of N‐type calcium currents in sympathetic neurons , 1998, The European journal of neuroscience.

[8]  Hans-Christian Pape,et al.  Novel vistas of calcium-mediated signalling in the thalamus , 2004, Pflügers Archiv.

[9]  E. Perez-Reyes,et al.  Molecular characterization of T-type calcium channels. , 2006, Cell calcium.

[10]  E. Ongini,et al.  Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. , 2002, European journal of pharmacology.

[11]  F. Bian,et al.  Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: An ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice , 2006, Brain Research.

[12]  V. Jevtovic-Todorovic,et al.  Mechanical and thermal antinociception in rats following systemic administration of mibefradil, a T-type calcium channel blocker , 2002, Brain Research.

[13]  K. Campbell,et al.  Attenuated pain responses in mice lacking CaV3.2 T‐type channels , 2007, Genes, brain, and behavior.

[14]  E. Perez-Reyes,et al.  Functional impact of alternative splicing of human T-type Cav3.3 calcium channels. , 2004, Journal of neurophysiology.

[15]  B. Hille,et al.  Substance P and somatostatin inhibit calcium channels in rat sympathetic neurons via different G protein pathwavs , 1993, Neuron.

[16]  J. Sandkühler,et al.  Pre‐ and postsynaptic contributions of voltage‐dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neurons , 2004, The European journal of neuroscience.

[17]  D. Bayliss,et al.  Low-Voltage-Activated Ca2+ Currents Are Generated by Members of the CavT Subunit Family (α1G/H) in Rat Primary Sensory Neurons , 1998, The Journal of Neuroscience.

[18]  R.,et al.  Low-Threshold Calcium Currents in Central Nervous System Neurons , 2003 .

[19]  Olivier Poirot,et al.  Silencing of the Cav3.2 T‐type calcium channel gene in sensory neurons demonstrates its major role in nociception , 2005, The EMBO journal.

[20]  Edmund M. Talley,et al.  Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels , 1999, The Journal of Neuroscience.

[21]  J. Offord,et al.  The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the Subunit of a Calcium Channel (*) , 1996, The Journal of Biological Chemistry.

[22]  Aaron M. Beedle,et al.  Agonist-independent modulation of N-type calcium channels by ORL1 receptors , 2004, Nature Neuroscience.

[23]  R. Llinás.  The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. , 1988, Science.

[24]  H. Pan,et al.  Signaling mechanisms of down-regulation of voltage-activated Ca2+ channels by transient receptor potential vanilloid type 1 stimulation with olvanil in primary sensory neurons , 2006, Neuroscience.

[25]  P. Lory,et al.  Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties. , 2001, Biophysical journal.

[26]  K. Campbell,et al.  Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. , 1997, Nature.

[27]  Bernd Nilius,et al.  Biophysics and structure-function relationship of T-type Ca2+ channels. , 2006, Cell calcium.

[28]  M. Christie,et al.  Inflammation reduces the contribution of N‐type calcium channels to primary afferent synaptic transmission onto NK1 receptor‐positive lamina I neurons in the rat dorsal horn , 2007, The Journal of physiology.

[29]  G. Lewin,et al.  A T-type calcium channel required for normal function of a mammalian mechanoreceptor , 2003, Nature Neuroscience.

[30]  A. Dolphin,et al.  Identification of the (cid:1) 2 - (cid:2) -1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin , 2006 .

[31]  C. Sommer,et al.  Nociceptin and its receptor in rat dorsal root ganglion neurons in neuropathic and inflammatory pain models: implications on pain processing , 2006, Journal of the peripheral nervous system : JPNS.

[32]  E. Perl,et al.  Differences in Ca2+ Channels Governing Generation of Miniature and Evoked Excitatory Synaptic Currents in Spinal Laminae I and II , 1998, The Journal of Neuroscience.

[33]  H. Saegusa,et al.  Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N‐type Ca2+ channel , 2001, The EMBO journal.

[34]  R. Neubig,et al.  Novel form of crosstalk between G protein and tyrosine kinase pathways. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y. Kuraishi,et al.  Nociceptin gene expression in rat dorsal root ganglia induced by peripheral inflammation , 1997, Neuroreport.

[36]  J. Kocsis,et al.  Voltage-gated calcium currents in axotomized adult rat cutaneous afferent neurons. , 2000, Journal of neurophysiology.

[37]  B. Collett,et al.  Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment , 2006, European journal of pain.

[38]  S. Hatakeyama,et al.  Differential nociceptive responses in mice lacking the alpha(1B) subunit of N-type Ca(2+) channels. , 2001, Neuroreport.

[39]  D. Bayliss,et al.  Cell-Specific Alterations of T-Type Calcium Current in Painful Diabetic Neuropathy Enhance Excitability of Sensory Neurons , 2007, The Journal of Neuroscience.

[40]  Dong Kwan Kim,et al.  Altered Nociceptive Response in Mice Deficient in the α1B Subunit of the Voltage-Dependent Calcium Channel , 2001, Molecular and Cellular Neuroscience.

[41]  K. Roche,et al.  Molecular determinants of NMDA receptor internalization , 2001, Nature Neuroscience.

[42]  A. Fox,et al.  Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size. , 1992, The Journal of physiology.

[43]  T. Snutch,et al.  Crosstalk between G proteins and protein kinase C mediated by the calcium channel α1 subunit , 1997, Nature.

[44]  P. Lory,et al.  Alternatively Spliced α1G (CaV3.1) Intracellular Loops Promote Specific T-Type Ca2+ Channel Gating Properties , 2001 .

[45]  B. Hille,et al.  Substance P and somatostatin inhibit calcium channels in rat sympathetic neurons via different G protein pathways. , 1993, Neuron.

[46]  H. Ueda,et al.  Enhanced Spinal Nociceptin Receptor Expression Develops Morphine Tolerance and Dependence , 2000, The Journal of Neuroscience.

[47]  M. Ehlers,et al.  Endocytosis and Degradative Sorting of NMDA Receptors by Conserved Membrane-Proximal Signals , 2004, The Journal of Neuroscience.

[48]  P. Barrett,et al.  T-type calcium channel regulation by specific G-protein betagamma subunits. , 2003, Nature.

[49]  Aaron M. Beedle,et al.  Expression of T‐type calcium channel splice variants in human glioma , 2004, Glia.

[50]  K. Campbell,et al.  CaV3.2 is the major molecular substrate for redox regulation of T‐type Ca2+ channels in the rat and mouse thalamus , 2006, The Journal of physiology.

[51]  D. T. Yue,et al.  G Protein-Gated Inhibitory Module of N-Type (CaV2.2) Ca2+ Channels , 2005, Neuron.

[52]  E. Perez-Reyes.  Molecular physiology of low-voltage-activated t-type calcium channels. , 2003, Physiological reviews.

[53]  P. Barrett,et al.  Stimulation of recombinant Ca(v)3.2, T-type, Ca(2+) channel currents by CaMKIIgamma(C). , 2002, The Journal of physiology.

[54]  Aaron M. Beedle,et al.  ORL1 receptor–mediated internalization of N-type calcium channels , 2006, Nature Neuroscience.

[55]  A. J. Castiglioni,et al.  Alternative splicing in the C‐terminus of CaV2.2 controls expression and gating of N‐type calcium channels , 2006, The Journal of physiology.

[56]  J. Hell,et al.  Biochemical properties and subcellular distribution of an N-type calcium hannel α1 subunit , 1992, Neuron.

[57]  C. Altier,et al.  Targeting Ca2+ channels to treat pain: T-type versus N-type. , 2004, Trends in pharmacological sciences.

[58]  T. Yaksh,et al.  Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. , 1994, The Journal of pharmacology and experimental therapeutics.

[59]  J. Luebke,et al.  Sensory neuron N-type calcium currents are inhibited by both voltage-dependent and -independent mechanisms , 1994, Pflügers Archiv.

[60]  F. Porreca,et al.  Reversal of experimental neuropathic pain by T-type calcium channel blockers , 2003, Pain.

[61]  P. Barrett,et al.  T-type calcium channel regulation by specific G-protein βγ subunits , 2003, Nature.

[62]  D. Hanck,et al.  A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. , 2006, Human molecular genetics.

[63]  P. Barrett,et al.  Stimulation of recombinant Cav3.2, T‐type, Ca2+ channel currents by CaMKIIγC , 2002 .

[64]  P. Lory,et al.  Plasma Membrane Expression of T-type Calcium Channel α1 Subunits Is Modulated by High Voltage-activated Auxiliary Subunits* , 2004, Journal of Biological Chemistry.

[65]  A. J. Castiglioni,et al.  Differential Role of N-Type Calcium Channel Splice Isoforms in Pain , 2007, The Journal of Neuroscience.

[66]  Gail Mandel,et al.  Nomenclature of Voltage-Gated Sodium Channels , 2000, Neuron.

[67]  A. J. Castiglioni,et al.  Alternative splicing controls G protein–dependent inhibition of N-type calcium channels in nociceptors , 2007, Nature Neuroscience.

[68]  S. Ikeda,et al.  A voltage-independent calcium current inhibitory pathway activated by muscarinic agonists in rat sympathetic neurons requires both Galpha q/11 and Gbeta gamma. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[69]  J. Bonifacino,et al.  Signals for sorting of transmembrane proteins to endosomes and lysosomes. , 2003, Annual review of biochemistry.

[70]  Patrick Delmas,et al.  Pharmacological Dissection and Distribution of NaN/Nav1.9, T-type Ca2+ Currents, and Mechanically Activated Cation Currents in Different Populations of DRG Neurons , 2007, The Journal of general physiology.

[71]  A. Verkhratsky,et al.  T-type calcium channels: the never ending story. , 2006, Cell calcium.

[72]  Denise S Walker,et al.  Direct binding of G-protein βλ complex to voltage-dependent calcium channels , 1997, Nature.

[73]  A. Dickenson,et al.  Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy , 2001, Pain.

[74]  R. Tsien,et al.  Nomenclature of Voltage-Gated Calcium Channels , 2000, Neuron.

[75]  신희섭,et al.  Thalamic control of visceral nociception mediated by T-type Ca2+ channels , 2003 .

[76]  M. Diversé-Pierluissi,et al.  Interaction of convergent pathways that inhibit N-type calcium currents in sensory neurons , 1995, Neuroscience.

[77]  P. Lory,et al.  Molecular biology of T-type calcium channels. , 2006, CNS & neurological disorders drug targets.

[78]  W. Agnew,et al.  Structure and alternative splicing of the gene encoding α1I, a human brain T calcium channel α1 subunit , 1999, Neuroscience Letters.

[79]  F. Ma,et al.  Expression of ORL1 mRNA in some brain nuclei in neuropathic pain rats , 2005, Brain Research.