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The Journal of Neuroscience, July 1, 1998, 18(13):4815-4824

Identification of the Amino Terminus of Neuronal Ca²⁺ Channel 1 Subunits 1B and 1E as an Essential Determinant of G-Protein Modulation

Karen M. Page, Carles Cantí, Gary J. Stephens, Nicholas S. Berrow, and Annette C. Dolphin

Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

We have examined the basis for G-protein modulation of the neuronal voltage-dependent calcium channels (VDCCs) 1E and 1B. A novel PCR product of 1E was isolated from rat brain. This contained an extended 5' DNA sequence and was subcloned onto the previously cloned isoform rbEII, giving rise to 1E_long whose N terminus was extended by 50 amino acids. VDCC 1 subunit constructs were co-expressed with the accessory 2- and 2a subunits in Xenopus oocytes and mammalian (COS-7) cells. The 1E_long showed biophysical properties similar to those of rbEII; however, when G-protein modulation of expressed 1 subunits was induced by activation of co-expressed dopamine (D2) receptors with quinpirole (100 nM) in oocytes, or by co-transfection of G12 subunits in COS-7 cells, 1E_long, unlike 1E(rbEII), was found to be G-protein-modulated, in terms of both a slowing of activation kinetics and a reduction in current amplitude. However, 1E_long showed less modulation than 1B, and substitution of the 1E_1-50 with the corresponding region of 1B_1-55 produced a chimera 1bEEEE, with G-protein modulation intermediate between 1E_long and 1B. Furthermore, deletion of the N-terminal 1-55 sequence from 1B produced 1BN_1-55, which could not be modulated, thus identifying the N-terminal domain as essential for G-protein modulation. Taken together with previous studies, these results indicate that the intracellular N terminus of 1E_1-50 and 1B_1-55 is likely to contribute to a multicomponent site, together with the intracellular I-II loop and/or the C-terminal tail, which are involved in G binding and/or in subsequent modulation of channel gating.

Key words: calcium channel; neuronal; G-protein; 1 subunit; G subunit; modulation

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18134815-10$05.00/0

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