G PROTEINS Enhancing Calcium Signaling

Tosetti et al. investigated the modulation of heterotrimeric guanosine 5'-triphosphate (GTP)-binding protein (G protein)-mediated inhibition of voltage-dependent Ca²⁺ channels in dorsal root ganglion cells (DRGs) and discovered two Ca²⁺-dependent mechanisms that could preferentially enhance Ca²⁺ signaling in particularly active neurons. Signaling by G proteins is terminated by the GTPase activity of the α subunit. Regulators of G protein signaling (RGS) accelerate this process; the mechanisms governing RGS activity, however, remain poorly understood. In chick DRGs, -aminobutyric acid (GABA) acts through Gα_o to inhibit Ca²⁺ channels. Tosetti et al. overexpressed variants of RGS3 and examined their effects on GABA-mediated inhibition of whole-cell Ca²⁺ currents. RGS3s produced a rapid attenuation--or desensitization--of GABA-mediated inhibition of Ca²⁺ currents. GABA-mediated inhibition of Ba²⁺ flux through Ca²⁺ channels was not affected, and an RGS3 mutant lacking an EF-hand (a Ca²⁺-binding domain) was ineffective. A gel mobility-shift assay indicated that Ca²⁺, but not Ba²⁺, bound intact RGS3. RGS3ss, an alternately spliced variant that lacked the EF hand did not elicit rapid desensitization, but did cause a slower form of Ca²⁺-dependent desensitization. Pharmacological analysis indicated that this slow desensitization depended on Ca²⁺ indirectly through calmodulin, rather than directly through Ca²⁺ binding. Thus, the two RGS variants are subject to different modes of Ca²⁺-dependent regulation. The authors suggest that the two isoforms could provide flexibility in Ca²⁺-dependent regulation of G protein-mediated inhibition of Ca²⁺ channels, and that Ca²⁺ regulation of RGS could provide a positive feedback mechanism to selectively enhance Ca²⁺ influx into particularly active neurons.

P. Tosetti, N. Pathak, M. H. Jacob, K. Dunlap, RGS3 mediates a calcium-dependent termination of G protein signaling in sensory neurons. Proc. Natl. Acad. Sci. U.S.A. 100, 7337-7342 (2003). [Abstract] [Full Text]

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VIRTUAL JOURNAL
RGS3 mediates a calcium-dependent termination of G protein signaling in sensory neurons

Patrizia Tosetti, Narendra Pathak, Michele H. Jacob, and Kathleen Dunlap (10 June 2003)
PNAS 100 (12), 7337. [DOI: 10.1073/pnas.1231837100]
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