Selective inhibition of Cav3.3 T-type calcium channels by Galphaq/11-coupled muscarinic acetylcholine receptors

Simple item page
dc.contributor.authorHildebrand, Michael E.
dc.contributor.authorDavid, Laurence S.
dc.contributor.authorHamid, Jawed
dc.contributor.authorMulatz, Kirk J.
dc.contributor.authorGarcía, Esperanza
dc.contributor.authorZamponi, Gerald W.
dc.contributor.authorSnutch, Terrance Preston
dc.date.accessioned2018-06-06T19:23:59Z
dc.date.available2018-06-06T19:23:59Z
dc.date.issued2007-07-20
dc.description.abstractT-type calcium channels play critical roles in controlling neuronal excitability, including the generation of complex spiking patterns and the modulation of synaptic plasticity, although the mechanisms and extent to which T-type Ca(2+) channels are modulated by G-protein-coupled receptors (GPCRs) remain largely unexplored. To examine specific interactions between T-type Ca(2+) channel subtypes and muscarinic acetylcholine receptors (mAChRS), the Cav3.1 (alpha(1G)), Cav3.2 (alpha(1H)), and Cav3.3 (alpha) T-type Ca(2+)(1I)channels were co-expressed with the M1 Galpha(q/11)-coupled mAChR. Perforated patch recordings demonstrate that activation of M1 receptors has a strong inhibitory effect on Cav3.3 T-type Ca(2+) currents but either no effect or a moderate stimulating effect on Cav3.1 and Cav3.2 peak current amplitudes. This differential modulation was observed for both rat and human T-type Ca(2+) channel variants. The inhibition of Cav3.3 channels by M1 receptors is reversible, use-independent, and associated with a concomitant increase in inactivation kinetics. Loss-of-function experiments with genetically encoded antagonists of Galpha and Gbetagamma proteins and gain-of-function experiments with genetically encoded Galpha subtypes indicate that M1 receptor-mediated inhibition of Cav3.3 occurs through Galpha(q/11). This is supported by experiments showing that activation of the M3 and M5 Galpha(q/11)-coupled mAChRs also causes inhibition of Cav3.3 currents, although Galpha(i)-coupled mAChRs (M2 and M4) have no effect. Examining Cav3.1-Cav3.3 chimeric channels demonstrates that two distinct regions of the Cav3.3 channel are necessary and sufficient for complete M1 receptor-mediated channel inhibition and represent novel sites not previously implicated in T-type channel modulation.en_US
dc.identifier.citationHildebrand, M. E., David, L. S., Hamid, J., Mulatz, K., Garcia, E., Zamponi, G. W., & Snutch, T. P. (2007). Selective inhibition of Cav3.3 T-type calcium channels by Galphaq/11-coupled muscarinic acetylcholine receptors. The Journal of Biological Chemistry, 282(29), 21043–55. https://doi.org/10.1074/jbc.M611809200en_US
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M611809200en_US
dc.identifier.issn0021-9258
dc.identifier.urihttp://hdl.handle.net/1880/106727
dc.language.isoenen_US
dc.publisherThe American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.publisher.departmentPhysiology & Pharmacologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.publisher.policyhttp://www.jbc.org/site/misc/edpolicy.xhtmlen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.titleSelective inhibition of Cav3.3 T-type calcium channels by Galphaq/11-coupled muscarinic acetylcholine receptorsen_US
dc.typejournal articleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Hildebrandt et al 2007.pdf
Size:
1.22 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.92 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Cumming School of Medicine Research & Publications