Chapter 6. Neuronal Calcium Channels

Abstract

Publisher Summary The understanding of the biology of neuronal calcium channels has developed significantly in recent times with the recognition of at least six subtypes of voltage-dependent calcium channels (VDCCs) found in the central nervous system (CNS). VDCC belong to a class of proteins that mediate ionic movements across excitable cell membranes in response to the changes in membrane potential. The subtypes of VDCC are commonly referred to as L, N, P, Q, R, and T that are divided into two groups, low voltage activated (LVA) and high voltage activated (HVA), on the basis of requirement of depolarization for activation. Molecular biology studies are revealing the subunit composition of these individual VDCC subtypes and allowing the development of cloned cell lines, expressing single populations of neuronal VDCCs. The chapter discusses the neuronal VDCCs of the N and P-Q families, because of their likely relevance to the neurotransmitter release. N-type channels are uniquely blocked by nanomolar concentrations of a peptide toxin, ω-CgTx-GVIA, found in the venom of a fish hunting mollusc, Conus geographus . Inhibition of a calcium channel by this toxin is widely accepted as being indicative of N type pharmacology. The inhibition is practically irreversible whereas that by another selective toxin, ω-CmTx-MVIIA from Conus magus, is readily reversible. There are known to be at least six a1 genes coding for the pore-forming proteins of HVA VDCCs. Expression of the cloned subunits in oocytes and mammalian cell lines is allowing comparison of the biophysics and pharmacologies of native and engineered channels. All cloned a1 subunits give rise to HVA channels. Expression of α 1A and α 1B gives rise to slowly inactivating channels whereas those expressed by α 1E genes are rapidly inactivating and more akin to R channels. Like R channels, α 1E expression leads to VDCCs that are insensitive to ω-CgTx-GVIA, ω-CmTx-MVIIC, and ω-Aga-IVA.