Transient receptor potential canonical 4 (TRPC4) forms non-selective cation channels implicated in the regulation of diverse physiological functions. Previously, TRPC4 was shown to be activated by the Gi/o subgroup of heterotrimeric G-proteins involving Gαi/o, rather than Gβγ, subunits. Because the lifetime and availability of Gα-GTP are regulated by regulators of G-protein signalling (RGS) and Gαi/o-Loco (GoLoco) domain-containing proteins via their GTPase-activating protein (GAP) and guanine-nucleotide-dissociation inhibitor (GDI) functions respectively, we tested how RGS and GoLoco domain proteins affect TRPC4 currents activated via Gi/o-coupled receptors. Using whole-cell patch-clamp recordings, we show that both RGS and GoLoco proteins [RGS4, RGS6, RGS12, RGS14, LGN or activator of G-protein signalling 3 (AGS3)] suppress receptor-mediated TRPC4 activation without causing detectable basal current or altering surface expression of the channel protein. The inhibitory effects are dependent on the GAP and GoLoco domains and facilitated by enhancing membrane targeting of the GoLoco protein AGS3. In addition, RGS, but not GoLoco, proteins accelerate desensitization of receptor-activation evoked TRPC4 currents. The inhibitory effects of RGS and GoLoco domains are additive and are most prominent with RGS12 and RGS14, which contain both RGS and GoLoco domains. Our data support the notion that the Gα, but not Gβγ, arm of the Gi/o signalling is involved in TRPC4 activation and unveil new roles for RGS and GoLoco domain proteins in fine-tuning TRPC4 activities. The versatile and diverse functions of RGS and GoLoco proteins in regulating G-protein signalling may underlie the complexity of receptor-operated TRPC4 activation in various cell types under different conditions.
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May 2016
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TGF-β2 induces actin stress fiber formation during the mesenchymal transition of human lens epithelial cells and αB-crystallin is essential for it. For further details see pp. 1455–1469. Image kindly provided by Ram Nagaraj. - PDF Icon PDF LinkFront Matter
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Research Article|
May 11 2016
Regulator of G-protein signalling and GoLoco proteins suppress TRPC4 channel function via acting at Gαi/o
Jae-Pyo Jeon;
Jae-Pyo Jeon
*Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
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Dhananjay P. Thakur;
Dhananjay P. Thakur
*Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
†Graduate Program in Cell and Regulatory Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
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Jin-bin Tian;
Jin-bin Tian
*Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
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Insuk So;
Insuk So
‡Department of Physiology, Seoul National University, College of Medicine, Seoul 110-799, South Korea
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Michael X. Zhu
Michael X. Zhu
1
*Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
†Graduate Program in Cell and Regulatory Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
December 08 2015
Revision Received:
March 15 2016
Accepted:
March 16 2016
Accepted Manuscript online:
March 17 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (10): 1379–1390.
Article history
Received:
December 08 2015
Revision Received:
March 15 2016
Accepted:
March 16 2016
Accepted Manuscript online:
March 17 2016
Citation
Jae-Pyo Jeon, Dhananjay P. Thakur, Jin-bin Tian, Insuk So, Michael X. Zhu; Regulator of G-protein signalling and GoLoco proteins suppress TRPC4 channel function via acting at Gαi/o. Biochem J 15 May 2016; 473 (10): 1379–1390. doi: https://doi.org/10.1042/BCJ20160214
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