Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca(2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3(-/-)/Nrl(-/-) mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca(2+) channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency.
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http://dx.doi.org/10.1074/jbc.M115.641159 | DOI Listing |
Elife
December 2024
Department of Physiology and Biophysics, University of Washington, Seattle, United States.
Cyclic nucleotide-binding domain (CNBD) ion channels play crucial roles in cellular-signaling and excitability and are regulated by the direct binding of cyclic adenosine- or guanosine-monophosphate (cAMP, cGMP). However, the precise allosteric mechanism governing channel activation upon ligand binding, particularly the energetic changes within domains, remains poorly understood. The prokaryotic CNBD channel SthK offers a valuable model for investigating this allosteric mechanism.
View Article and Find Full Text PDFCurr Biol
November 2024
Life Sciences Institute, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:
Shear stress sensing represents a vital mode of mechanosensation. Previous efforts have mainly focused on characterizing how various cell types-for example, vascular endothelial cells-sense shear stress arising from fluid flow within the animal body. How animals sense shear stress derived from their external environment, however, is not well understood.
View Article and Find Full Text PDFPeerJ
October 2024
Jiangxi Provincial Key Laboratory of Natural Active Pharmaceutical Constituents, Department of Chemistry and Bioengineering, Yichun University, Yichun, China.
Mammalian sperm are characterized as specialized cells, as their transcriptional and translational processes are largely inactive. Emerging researches indicate that Ca serves as a crucial second messenger in the modulation of various sperm physiological processes, such as capacitation, hyperactivation, and the acrosome reaction. Specifically, sperm-specific calcium channels, including CatSper, voltage-gated calcium channels (VGCCs), store-operated calcium channels (SOCCs), and cyclic nucleotide-gated (CNG) channels, are implicated in the regulation of calcium signaling in mammalian sperm.
View Article and Find Full Text PDFbioRxiv
October 2024
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195.
Cyclic nucleotide-binding domain (CNBD) ion channels play crucial roles in cellular-signaling and excitability and are regulated by the direct binding of cyclic adenosine- or guanosine-monophosphate (cAMP, cGMP). However, the precise allosteric mechanism governing channel activation upon ligand binding, particularly the energetic changes within domains, remains poorly understood. The prokaryotic CNBD channel SthK offers a valuable model for investigating this allosteric mechanism.
View Article and Find Full Text PDFNat Commun
September 2024
Department of Anesthesiology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, USA.
The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels. It inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. The prokaryotic SthK channel from Spirochaeta thermophila shares features with CNG and HCN channels and is an established model for this channel family.
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