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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/C573    most recent 00219.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Toro-Castillo, C. Articles by Meza, U. Search for Related Content PubMed PubMed Citation Articles by Toro-Castillo, C. Articles by Meza, U.

RECEPTORS AND SIGNAL TRANSDUCTION

Muscarinic modulation of Ca_v2.3 (R-type) calcium channels is antagonized by RGS3 and RGS3T

¹Facultad de Medicina, Departamento de Fisiología y Farmacología, ³Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México; and ²Department of Biology, Utah State University, Logan, Utah

Submitted 30 April 2006 ; accepted in final form 13 July 2006

Ca²⁺ influx through voltage-gated R-type (Ca_V2.3) Ca²⁺ channels is important for hormone and neurotransmitter secretion and other cellular events. Previous studies have shown that Ca_V2.3 is both inhibited and stimulated through signaling mechanisms coupled to muscarinic ACh receptors. We previously demonstrated that muscarinic stimulation of Ca_V2.3 is blocked by regulator of G protein signaling (RGS) 2. Here we investigated whether muscarinic inhibition of Ca_V2.3 is antagonized by RGS3. RGS3 is particularly interesting because it contains a lengthy (380 residue) amino-terminal domain of uncertain physiological function. Ca_V2.3, M₂ muscarinic ACh receptors (M₂R), and various deletion mutants of RGS3, including its native isoform RGS3T, were expressed in HEK293 cells, and agonist-dependent inhibition of Ca_V2.3 was quantified using whole cell patch-clamp recordings. Full-length RGS3, RGS3T, and the core domain of RGS3 were equally effective in antagonizing inhibition of Ca_V2.3 through M₂R. These results identify RGS3 and RGS3T as potential physiological regulators of R-type Ca²⁺ channels. Furthermore, they suggest that the signaling activity of RGS3 is unaffected by its extended amino-terminal domain. Confocal microscopy was used to examine the intracellular locations of four RGS3-enhanced green fluorescent protein fusion proteins. The RGS3 core domain was uniformly distributed throughout both cytoplasm and nucleus. By contrast, full-length RGS3, RGS3T, and the amino-terminal domain of RGS3 were restricted to the cytoplasm. These observations suggest that the amino terminus of RGS3 may serve to confine it to the cytoplasmic compartment where it can interact with cell surface receptors, heterotrimeric G proteins, and other signaling proteins.

calcium channels; regulator of G protein signaling proteins; muscarinic acetylcholine receptors; enhanced green fluorescent protein-fusion proteins; voltage-gated R-type calcium channels