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J Neurophysiol 85: 816-827, 2001;
0022-3077/01 $5.00
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The Journal of Neurophysiology Vol. 85 No. 2 February 2001, pp. 816-827
Copyright ©2001 by the American Physiological Society

Biophysical Properties, Pharmacology, and Modulation of Human, Neuronal L-Type (alpha 1D, CaV1.3) Voltage-Dependent Calcium Currents

D. C. Bell,1 A. J. Butcher,1 N. S. Berrow,1 K. M. Page,1 P. F. Brust,2 A. Nesterova,2 K. A. Stauderman,2 G. R. Seabrook,3 B. Nürnberg,4 and A. C. Dolphin1

 1Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom;  2Merck Research Laboratories, La Jolla, California 92307;  3Abteilung Pharmakologie und Toxikologie, Universität Ulm and Institut für Pharmakologie, Freie Universität, D-14195 Berlin, Germany; and  4Merck, Sharp and Dohme, Neuroscience Research Centre, Harlow CM20 2QR, United Kingdom

Bell, D. C., A. J. Butcher, N. S. Berrow, K. M. Page, P. F. Brust, A. Nesterova, K. A. Stauderman, G. R. Seabrook, B. Nürnberg, and A. C. Dolphin. Biophysical Properties, Pharmacology, and Modulation of Human, Neuronal L-Type (alpha 1D, CaV1.3) Voltage-Dependent Calcium Currents. J. Neurophysiol. 85: 816-827, 2001. Voltage-dependent calcium channels (VDCCs) are multimeric complexes composed of a pore-forming alpha 1 subunit together with several accessory subunits, including alpha 2delta , beta , and, in some cases, gamma  subunits. A family of VDCCs known as the L-type channels are formed specifically from alpha 1S (skeletal muscle), alpha 1C (in heart and brain), alpha 1D (mainly in brain, heart, and endocrine tissue), and alpha 1F (retina). Neuroendocrine L-type currents have a significant role in the control of neurosecretion and can be inhibited by GTP-binding (G-) proteins. However, the subunit composition of the VDCCs underlying these G-protein-regulated neuroendocrine L-type currents is unknown. To investigate the biophysical and pharmacological properties and role of G-protein modulation of alpha 1D calcium channels, we have examined calcium channel currents formed by the human neuronal L-type alpha 1D subunit, co-expressed with alpha 2delta -1 and beta 3a, stably expressed in a human embryonic kidney (HEK) 293 cell line, using whole cell and perforated patch-clamp techniques. The alpha 1D-expressing cell line exhibited L-type currents with typical characteristics. The currents were high-voltage activated (peak at +20 mV in 20 mM Ba2+) and showed little inactivation in external Ba2+, while displaying rapid inactivation kinetics in external Ca2+. The L-type currents were inhibited by the 1,4 dihydropyridine (DHP) antagonists nifedipine and nicardipine and were enhanced by the DHP agonist BayK S-(-)8644. However, alpha 1D L-type currents were not modulated by activation of a number of G-protein pathways. Activation of endogenous somatostatin receptor subtype 2 (sst2) by somatostatin-14 or activation of transiently transfected rat D2 dopamine receptors (rD2long) by quinpirole had no effect. Direct activation of G-proteins by the nonhydrolyzable GTP analogue, guanosine 5'-0-(3-thiotriphospate) also had no effect on the alpha 1D currents. In contrast, in the same system, N-type currents, formed from transiently transfected alpha 1B/alpha 2delta -1/beta 3, showed strong G-protein-mediated inhibition. Furthermore, the I-II loop from the alpha 1D clone, expressed as a glutathione-S-transferase (GST) fusion protein, did not bind Gbeta gamma , unlike the alpha 1B I-II loop fusion protein. These data show that the biophysical and pharmacological properties of recombinant human alpha 1D L-type currents are similar to alpha 1C currents, and these currents are also resistant to modulation by Gi/o-linked G-protein-coupled receptors.




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