Distinctive pharmacology and kinetics of cloned neuronal Ca²⁺ channels and their possible counterparts in mammalian CNS neurons

Abstract

This paper provides a brief overview of the diversity of voltage-gated Ca²⁺ channels and our recent work on neuronal Ca²⁺ channels with novel pharmacological and biophysical properties that distinguish them from L, N, P or T-type channels. The Ca²⁺ channel α₁ subunit known as α_1A or BI [Mori Y., Friedrich T., Kim M.-S., Mikami A., Nakai J., Ruth P., Bosse E., Hofmann F., Flockerzi V., Furuichi T., Mikoshiba K., Imoto K., Tanabe T. and Numa S. (1991) Nature350, 398–402] is generally assumed to encode the P-type Ca²⁺ channel. However, we find that α_1A expressed in Xenopus oocytes differs from P-type channels in its kinetics of inactivation and its degree of sensitivity to block by the peptide toxins ω-Aga-IVA and ω-CTx-MVIIC [Sather W. A., Tanabe T., Zhang J.-F., Mori Y., Adams M. E. and Tsien R. W. (1993) Neuron11, 291–303]. Thus, α_1A is capable of generating a Ca²⁺ channel with characteristics quite distinct from P-type channels. Doe-1, recently cloned from the forebrain of a marine ray, is another α₁ subunit which exemplifies a different branch of the Ca²⁺ channel family tree [Home W. A., Ellinor P. T., Inman I., Zhou M., Tsien R. W. and Schwarz T. L. (1993) Proc. Natn. Acad. Sci. U.S.A. 90, 3787–3791]. When expressed in Xenopus oocytes, doe-1 forms a high voltage-activated (HVA) Ca²⁺ channel [Ellinor P. T., Zhang J.-F., Randall A. D., Zhou M., Schwarz T. L., Tsien R. W. and Home W. (1993) Nature363, 455–458]. It inactivates more rapidly than any previously expressed calcium channel and is not blocked by dihydropyridine antagonists or ω-Aga-IVA. Doe-1 current is reduced by ω-CTx-GVIA, but the inhibition is readily reversible and requires micromolar toxin, in contrast to this toxin's potent and irreversible block of N-type channels. Doe-1 shows considerable sensitivity to block by Ni²⁺ or Cd²⁺. We have identified components of Ca²⁺ channel current in rat cerebellar granule neurons with kinetic and pharmacological features similar to α_1A and doe-1 in oocytes [Randall A. D., Wendland B., Schweizer F., Miljanich G., Adams M. E. and Tsien R. W. (1993) Soc. Neurosci. Abstr.19, 1478]. The doe-1-like component (R-type current) inactivates much more quickly than L, N or P-type channels, and also differs significantly in its pharmacology. The rapid inactivation and slow repriming of R-type current would make its contribution to Ca²⁺ entry strongly frequency-dependent.