TABLE 6

Ca_V2.1 channels

Channel name	Ca_v2.1
Description	Voltage-gated calcium channel α₁ subunit
Other names	α_1A, P-type, Q-type, rbA-I (in rat)¹; BI-1, BI-2 (in rabbit)²
Molecular information	Human: 2510aa, AF004883, 2662aa, AF004884, chr. 19p13, CACNA1A
	Rat: 2212aa, M64373
	Mouse: 2165aa, NM007578, NP031604
	Rabbit: 2273aa, X57476 (see “Comments”)
Associated subunits	α₂δ, β, possibly γ
Functional assays	Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release
Current	I_Ca,P, I_Ca,Q
Conductance	9, 14, 19pS (P-type, cerebellar Purkinje neurones)⁴; 16–17pS (for α_1A/α₂δ/β in Xenopus oocytes)²^,⁵^,⁶
Ion selectivity	Ba²⁺ > Ca²⁺
Activation	V_a = –5 mV for native P-type, V_a = –11 mV for native Q-type (with 5 mM Ba²⁺ charge carrier)⁷
	V_a = –4.1 mV for rat α_1A-a/α₂δ/β₄
	V_a = +2.1 mV for rat α_1A-b/α₂δ/β₄ (with 5 mM Ba²⁺ charge carrier)⁶
	V_a = +9.5 mV; τ_a = 2.2 ms at +10 mV for human α_1A-1/α₂δ/β_1b in HEK293 cells (with 15 mM Ba²⁺ charge carrier)³
Inactivation	V_h = –17.2 mV for α_1A-a/α₂δ/β₄; V_h = –1.6 mV for α_1A-b/α₂δ/β₄ (with 5 mM Ba²⁺ charge carrier); V_h = –17 mV, τ_h = 690 ms at +10 mV human α_1A-1/α₂δ/β_1b in HEK293 cells (with 15 mM Ba²⁺ charge carrier)³; τ_h > 1 s at 0 mV native P-type (with 5 mM Ba²⁺ charge carrier)⁷ (see “Comments”)
Activators	None
Gating modifiers	ω-agatoxin IVA (P-type K_d = 1–3 nM⁸; Q-type K_d ∼ 100–200 nM⁵^,⁹), ω-agatoxin IVB⁶
Blockers	ω-conotoxin MVIIC⁸; other blockers include piperidines, substituted diphenylbutylpiperidines, piperazines, volatile anesthetics, gabapentin, mibefradil, and peptide toxins DW13.3 and ω-conotoxin SVIB²¹^,²²^,²³^,²⁴^,²⁵^,²⁶ (see “Comments”)
Radioligands	[¹²⁵I]ω-conotoxin MVIIC
Channel distribution	Neurons (presynaptic terminals, dendrites, some cell bodies), heart, pancreas, pituitary
Physiological functions	Neurotransmitter release in central neurons and neuromuscular junction; excitation-secretion coupling in pancreatic β-cells
Mutations and pathophysiology	Missense mutations in IS4-IS5, IIS4-IIS6, IIIS4-IIIS6, and IVS4-IVS6 cause FHM²⁷; a common feature among FHM mutations is an apparent gain-of-function phenotype as a result of a shift in V_50act to more hyperpolarized potentials (an increased probability of opening at the single channel level)²⁸^,²⁹; other effects include a decrease in maximal current density at the whole-cell level and alterations of synaptic transmission²⁸^,²⁹^,³⁰^,³¹; point mutations in IIS1, IIS6-IIIS2, IIIS5-IIIS6, and IVS1-IVS5 cause episodic ataxia type-2, a polyglutamine expansion in the carboxyl region causes spinocerebellar ataxia type-6, and mutation of IS5-IS6 and IVS6 causes episodic and progressive ataxia¹⁰^,¹¹^,¹²^,²⁷
Pharmacological significance	Peptide toxins that selectively inhibit Ca_v2.1 channel block a significant portion of neurotransmission in the mammalian CNS¹³; block of Ca_v2.1 channels inhibits the late-phase formalin response and inflammatory pain but has no significant effect on mechanical allodynia or thermal hyperalgesia¹⁴^,¹⁵^,¹⁶^,¹⁷; mice lacking a functional Ca_v2.1 gene exhibit cerebellar atrophy, severe muscle spasms, and ataxia and usually die by 3 to 4 weeks postnatal¹⁸^,¹⁹
Comments	Rates of inactivation and V_h are differentially affected by coexpression with β_1b, β_2a, β₃, or β₄ subunits, as well as by alternative splicing of the α_1A subunit; identified regions of alternative splicing include the domain I-II linker, domain II-III linker, IVS3-IVS4, and the carboxyl terminus¹^,²^,⁶^,³²^,³³^,³⁴; whole-cell currents with P-type kinetics seem to be conducted by the α_1A-b splice variant coexpressed with any of the β subunits or by the α_1A-a splice variant coexpressed with the β_2a subunit⁶^,⁷^,²⁰; whole-cell currents with Q-type kinetics seem to be encoded by α_1A-a coexpressed with any of the β_1b, β₃, or β₄ subunits⁶^,²⁰; whole-cell currents with Q-type pharmacology seem to be encoded by α_1A splice variants containing Asp Pro residues in the domain IV S3-S4 linker, whereas whole-cell currents with P-type pharmacology seem to be conducted by α_1A splice variants missing Asp Pro residues in IV S3-S4 linker³^,⁶; alternative splicing also alters current density, current-voltage relations, calcium/calmodulin-dependent facilitation, sensitivity to mibefradil, and binding to intracellular synaptic proteins such as Mint1, CASK, syntaxin, and SNAP-25²⁶^,³²^,³⁶

aa, amino acids; chr., chromosome; HEK, human embryonic kidney; FHM, familial hemiplegic migraine; CNS, central nervous system.
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