TABLE 3

Cav distribution, toxin inhibitors and potential effects of inhibition

Cav IsoformDistributionSelective Toxin InhibitorsEffects/Side Effects of InhibitionReferences
Cav1.1–1.4 (L-type) (CACNA1S or C or D or F)Skeletal muscle (1.1), (T-tubules), Cardiac muscle (1.2–1.3), smooth muscle (1.2), CNS (1.1–1.3), DRG (1.2–1.4), retina (1.4) lymphocytes (1.2–1.4), GIT (1.2), cochlea (1.3).None known (dihydropyridines)Widespread effects on cardiovascular system, 1.2 implicated in neuropathic pain in spinal cord.Kim et al., 2001; Catterall et al., 2005b, 2007; Fossat et al., 2010
Cav2.1 (P/Q type) (CACNA1A) splice variantsBrain, spinal cord, sympathetic neurons, DRG, endocrine cells, contribution to presynaptic neurotransmitter release at CNS, PNS, and neuromuscular junction.ω-Conotoxins MVIIC ∼ MVIID > CVIB > CVIC ≫ MVIIA > GVIA ≫ CVIDMutations in several neurological disorders, blockers produce partial inhibition of synaptic transmission. Peripheral side effects expected from autonomic and neuromuscular block.Bourinet et al., 1999; Nudler et al., 2003; Catterall et al., 2005b, 2007 (For selectivity see Table 4.)
Spider toxins: ω-agatoxin IVA
Cav2.2 (CACNA1B) splice variantsBrain, spinal cord, sympathetic neurons, DRG, contribution to presynaptic neurotransmitter release in CNS and PNS.ω-Conotoxins CVIE = CVID = GVIA ≫ CVIA ∼ MVIIA > CVIB ∼ CVICBlockers produce inhibition of synaptic transmission throughout the nervous system.Catterall et al., 2005b, 2007 (For selectivity see Table 4.)
Cav2.3 (CACNA1E) splice variantsBrain, spinal cord, sympathetic neurons, DRG, minor role in presynaptic neurotransmitter release in CNS and PNS, synaptic plasticity.No conotoxinsBlockers modulate synaptic plasticity at some brain synapses.Murakami et al., 2004; Catterall et al., 2005b, 2007; Matthews et al., 2007 (For selectivity see Table 4.)
Spider: SNX-482
Cav3.1 (CACNA1G)Brain neurons localized to soma and dendrites. High expression in cerebellum and thalamus. Modulates action potential firing. Ovary, placenta, heart.No conotoxins (pimozide, mibefradil, TTA-P2)Small-molecule modulators may be useful for some CNS neurological disorders.Catterall et al., 2005b, 2007; Yaksh, 2006; Triggle, 2007; Zamponi et al., 2009
Cav3.2 (CACNA1H)CNS, DRG neurons: localized to soma and dendrites. Modulates action potential firing. Also heart, liver, kidney, lung, skeletal muscle, pancreas.No conotoxinsPain modulation. Relaxation of coronary arteries, potential side effects from actions in other tissues.Catterall et al., 2005b, 2007; Yaksh, 2006; Triggle, 2007; Zamponi et al., 2009; Choe et al., 2011
Scorpion: kurtoxin (pimozide, mibefradil, Z123212,a TTA-P2)
Cav3.3 (CACNA1I)CNS neurons: localized to soma and dendrites. Modulates action potential firing.No conotoxins (pimozide, TTA-P2, mibefradil very weak)Presumably many side effects.Catterall et al., 2005b, 2007; Yaksh, 2006; Triggle, 2007; Zamponi et al., 2009
  • a Z123212 (Hildebrand et al., 2011) also targets sodium channels.

    PNS, peripheral nervous system; TTA-P2, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide.