DISTINCTIVE PHARMACOLOGY AND KINETICS OF CLONED NEURONAL CA2+ CHANNELS AND THEIR POSSIBLE COUNTERPARTS IN MAMMALIAN CNS NEURONS

This paper provides a brief overview of the diversity of voltage-gated Ca2+ channels and our recent work on neuronal Ca2+ channels with nove l pharmacological and biophysical properties that distinguish them fro m L, N, P or T-type channels. The Ca2+ channel alpha1 subunit known as alpha1A 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) Nature 350, 398-402] is gene rally assumed to encode the P-type Ca2+ channel. However, we find that alpha1A 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 omega-Aga-IVA and omega-CTx-MVIIC [Sather W. A., T anabe T., Zhang J.-F., Mori Y., Adams M. E. and Tsien R. W. (1993) Neu ron 11, 291-303]. Thus, alpha1A is capable of generating a Ca2+ channe l with characteristics quite distinct from P-type channels. Doe-1, rec ently cloned from the forebrain of a marine my, is another alpha1 subu nit which exemplifies a different branch of the Ca2+ channel family tr ee [Home W. A., Ellinor P. T., Inman I., Zhou M., Tsien R. W. and Schw arz T. L. (1993) Proc. Natn. Acad. Sci. U.S.A. 90, 3787-3791]. When ex pressed in Xenopus oocytes, doe-1 forms a high voltage-activated (HVA) Ca2+ channel [Ellinor P. T., Zhang J.-F., Randall A. D., Zhou M., Sch warz T. L., Tsien R. W. and Home W. (1993) Nature 363, 455-458]. It in activates more rapidly than any previously expressed calcium channel a nd is not blocked by dihydropyridine antagonists or omega-Aga-IVA. Doe -I current is reduced by omega-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 conside rable sensitivity to block by Ni2+ or Cd2+. We have identified compone nts of Ca2+ channel current in mt cerebellar granule neurons with kine tic and pharmacological features similar to alpha1A and doe-1 in oocyt es [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-li ke 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 ma ke its contribution to Ca2+ entry strongly frequency-dependent.