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Cell Calcium. 2017 Sep;66:1-9. doi: 10.1016/j.ceca.2017.05.008. Epub 2017 May 15.

Regulation of L-type CaV1.3 channel activity and insulin secretion by the cGMP-PKG signaling pathway.

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FES Iztacala UNAM, Tlalnepantla De Baz, Mexico.
Departamento de Biología Celular, Cinvestav-IPN, Ciudad de México, Mexico.
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Department of Biological Sciences, University of New Hampshire, Durham, NH, USA.
Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría, Ramón de la Fuente Muñiz, Ciudad de México, Mexico.
Department of Ophtalmology and Molecular Pharmacology & Therapeutics, Loyola University, Chicago, Strich School of Medicine, Maywood, IL, USA.
Departamento de Biología Celular, Cinvestav-IPN, Ciudad de México, Mexico. Electronic address:


cGMP is a second messenger widely used in the nervous system and other tissues. One of the major effectors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG), which catalyzes the phosphorylation of a variety of proteins including ion channels. Previously, it has been shown that the cGMP-PKG signaling pathway inhibits Ca2+ currents in rat vestibular hair cells and chromaffin cells. This current allegedly flow through voltage-gated CaV1.3L-type Ca2+ channels, and is important for controlling vestibular hair cell sensory function and catecholamine secretion, respectively. Here, we show that native L-type channels in the insulin-secreting RIN-m5F cell line, and recombinant CaV1.3 channels heterologously expressed in HEK-293 cells, are regulatory targets of the cGMP-PKG signaling cascade. Our results indicate that the CaVα1 ion-conducting subunit of the CaV1.3 channels is highly expressed in RIN-m5F cells and that the application of 8-Br-cGMP, a membrane-permeable analogue of cGMP, significantly inhibits Ca2+ macroscopic currents and impair insulin release stimulated with high K+. In addition, KT-5823, a specific inhibitor of PKG, prevents the current inhibition generated by 8-Br-cGMP in the heterologous expression system. Interestingly, mutating the putative phosphorylation sites to residues resistant to phosphorylation showed that the relevant PKG sites for CaV1.3 L-type channel regulation centers on two amino acid residues, Ser793 and Ser860, located in the intracellular loop connecting the II and III repeats of the CaVα1 pore-forming subunit of the channel. These findings unveil a novel mechanism for how the cGMP-PKG signaling pathway may regulate CaV1.3 channels and contribute to regulate insulin secretion.


Cav channels; Insulin; L-type channels; PKG; Rin-m5F cells; cGMP

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