Abstract
Low-voltage-activated (LVA) T-type calcium channels have a wide tissue distribution and have well-documented roles in the control of action potential burst generation and hormone secretion1. In neurons of the central nervous system and secretory cells of the adrenal and pituitary, LVA channels are inhibited by activation of G-protein-coupled receptors that generate membrane-delimited signals2,3,4,5, yet these signals have not been identified. Here we show that the inhibition of α1H (Cav3.2), but not α1G (Cav3.1) LVA Ca2+ channels is mediated selectively by β2γ2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the α1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated α1G channels confers β2γ2-dependent inhibition. βγ reduces channel activity independent of voltage, a mechanism distinct from the established βγ-dependent inhibition of non-L-type high-voltage-activated channels of the Cav2 family6,7. These studies identify the α1H channel as a new effector for G-protein βγ subunits, and highlight the selective signalling roles available for particular βγ combinations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Perez-Reyes, E. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol. Rev. 83, 117–161 (2003)
Lledo, P. M., Legendre, P., Israel, J. M. & Vincent, J. D. Dopamine inhibits two characterized voltage-dependent calcium currents in identified rat lactotroph cells. Endocrinology 127, 990–1001 (1990)
Lledo, P. M., Homburger, V., Bockaert, J. & Vincent, J. D. Differential G protein-mediated coupling of D2 dopamine receptors to K+ and Ca2+ currents in rat anterior pituitary cells. Neuron 8, 455–463 (1992)
Marchetti, C., Carbone, E. & Lux, H. D. Effects of dopamine and noradrenaline on Ca channels of cultured sensory and sympathetic neurons of chick. Pflügers Arch. Eur. J. Physiol. 406, 104–111 (1986)
Williams, P. J., MacVicar, B. A. & Pittman, Q. J. Synaptic modulation by dopamine of calcium currents in rat pars intermedia. J. Neurosci. 10, 757–763 (1990)
Bean, B. P. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340, 153–156 (1989)
Ikeda, S. R. Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380, 255–258 (1996)
Logothetis, D. E., Kurachi, Y., Galper, J., Neer, E. J. & Clapham, D. E. The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325, 321–326 (1987)
Herlitze, S. et al. Modulation of Ca2+ channels by G-protein βγ subunits. Nature 380, 258–262 (1996)
De Waard, M. et al. Direct binding of G-protein βγ complex to voltage-dependent calcium channels. Nature 385, 446–450 (1997)
Qin, N., Platano, D., Olcese, R., Stefani, E. & Birnbaumer, L. Direct interaction of Gβγ with a C-terminal Gβγ-binding domain of the Ca2+ channel α1 subunit is responsible for channel inhibition by G protein-coupled receptors. Proc. Natl Acad. Sci. USA 94, 8866–8871 (1997)
Zhang, J. F., Ellinor, P. T., Aldrich, R. W. & Tsien, R. W. Multiple structural elements in voltage-dependent Ca2+ channels support their inhibition by G proteins. Neuron 17, 991–1003 (1996)
Zamponi, G. W., Bourinet, E., Nelson, D., Nargeot, J. & Snutch, T. P. Crosstalk between G proteins and protein kinase C mediated by the calcium channel α1 subunit. Nature 385, 442–446 (1997)
Jarvis, S. E. & Zamponi, G. W. Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex. Trends Pharmacol. Sci. 22, 519–525 (2001)
Catterall, W. A. Structure and regulation of voltage-gated calcium channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000)
Cooper, C. B. et al. Cross-talk between G-protein and protein kinase C modulation of N-type calcium channels is dependent on the G-protein β subunit isoform. J. Biol. Chem. 275, 40777–40781 (2000)
Downes, G. B. & Gautam, N. The G protein subunit gene families. Genomics 62, 544–552 (1999)
Lei, Q. et al. Activation and inhibition of G protein-coupled inwardly rectifying potassium (Kir3) channels by G protein βγ subunits. Proc. Natl Acad. Sci. USA 97, 9771–9776 (2000)
Fishman, M. C. & Spector, I. Potassium current suppression by quinidine reveals additional calcium currents in neuroblastoma cells. Proc. Natl Acad. Sci. USA 78, 5245–5249 (1981)
Beguin, P. et al. Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411, 701–706 (2001)
Chen, J. et al. A region of adenylyl cyclase 2 critical for regulation by G protein βγ subunits. Science 268, 1166–1169 (1995)
Safa, P., Boulter, J. & Hales, T. G. Functional properties of Cav1.3 (α1D) L-type Ca2+ channel splice variants expressed by rat brain and neuroendocrine GH3 cells. J. Biol. Chem. 276, 38727–38737 (2001)
Schrier, A. D., Wang, H., Talley, E. M., Perez-Reyes, E. & Barrett, P. Q. α1H T-type Ca2+ channel is the predominant subtype expressed in bovine and rat zona glomerulosa. Am. J. Physiol. Cell Physiol. 280, C265–C272 (2001)
Bird, I. M. et al. Human NCI-H295 adrenocortical carcinoma cells: A model for angiotensin-II-responsive aldosterone secretion. Endocrinology 133, 1555–1561 (1993)
Koch, W. J., Hawes, B. E., Inglese, J., Luttrell, L. M. & Lefkowitz, R. J. Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G βγ-mediated signaling. J. Biol. Chem. 269, 6193–6197 (1994)
Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. & Caron, M. G. Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998)
Sunahara, R. K., Dessauer, C. W. & Gilman, A. G. Complexity and diversity of mammalian adenylyl cyclases. Annu. Rev. Pharmacol. Toxicol. 36, 461–480 (1996)
Drolet, P. et al. Inhibition of the T-type Ca2+ current by the dopamine D1 receptor in rat adrenal glomerulosa cells: Requirement of the combined action of the G βγ protein subunit and cyclic adenosine 3′,5′-monophosphate. Mol. Endocrinol. 11, 503–514 (1997)
Kozasa, T. in G Proteins, Techniques for Analysis (ed. Manning, D. R.) 23–38 (CRC, Boca Raton, Florida, 1999)
Graber, S. G., Lindorfer, M. A. & Garrison, J. C. Expression and purification of G-protein βγ subunits using a baculovirus expression system. J. Methods Neurosci. 29, 207–226 (1996)
Acknowledgements
We thank E. Perez-Reyes for α1H and α1G clones, the University of Virginia Flow-Cytometry Core for FACS analysis, and G. MacCleery for help with βγ purification. This study was supported by grants (to P.Q.B. and J.C.G.) from the NIH. J.T.W. was supported by predoctoral fellowships from the University of Virginia Cardiovascular Research Center and the American Heart Association.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
Wolfe, J., Wang, H., Howard, J. et al. T-type calcium channel regulation by specific G-protein βγ subunits. Nature 424, 209–213 (2003). https://doi.org/10.1038/nature01772
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01772
This article is cited by
-
The T-type calcium channelosome
Pflügers Archiv - European Journal of Physiology (2024)
-
Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review
Molecular Brain (2020)
-
Neuronal Cav3 channelopathies: recent progress and perspectives
Pflügers Archiv - European Journal of Physiology (2020)
-
A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca2+ channels
Scientific Reports (2019)
-
Contributions of T-Type Voltage-Gated Calcium Channels to Postsynaptic Calcium Signaling within Purkinje Neurons
The Cerebellum (2012)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.