Post-Translational Modification and Natural Mutation of TRPC Channels

Abstract

Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca2+ permeability and are activated by a wide spectrum of stimuli. These channels are ubiquitously expressed in different tissues and organs in mammals and exert a variety of physiological functions. Post-translational modifications (PTMs) including phosphorylation, N-glycosylation, disulfide bond formation, ubiquitination, S-nitrosylation, S-glutathionylation, and acetylation play important roles in the modulation of channel gating, subcellular trafficking, protein-protein interaction, recycling, and protein architecture. PTMs also contribute to the polymodal activation of TRPCs and their subtle regulation in diverse physiological contexts and in pathological situations. Owing to their roles in the motor coordination and regulation of kidney podocyte structure, mutations of TRPCs have been implicated in diseases like cerebellar ataxia (moonwalker mice) and focal and segmental glomerulosclerosis (FSGS). The aim of this review is to comprehensively integrate all reported PTMs of TRPCs, to discuss their physiological/pathophysiological roles if available, and to summarize diseases linked to the natural mutations of TRPCs.

The role of activation of two different sGC binding sites by NO‐dependent and NO‐independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes

“…This series of experiments tested an alternative mechanism for modulation of the inward nonselective cation current, apart from the receptor‐operated mode, in which, NO directly modifies free sulfhydryl groups, induces S‐nitrosylation, and opens the gate of the channel (Liu et al, 2020 ). An inhibitor of S‐nitrosylation ‐ ascorbic acid (Ohtani et al, 2012 ) at concentrations 1 and 10 μmol/L was used to demonstrate nitric oxide (NO)‐induced S‐nitrosylation.…”

TRP Channels Interactome as a Novel Therapeutic Target in Breast Cancer

“…As we previously discussed, the TRP channels interactome could be used as a novel therapeutic target in breast cancer by promoting or interrupting the discussed interactions, thus modulating channel activity and associated signaling pathways. As with others proteins, TRP channels can also be regulated by a plethora of posttranslational modifications (PTM), which provide spatialtemporal control of several processes such as ion channel inactivation, activation, trafficking, endocytosis, and degradation (358)(359)(360). Interestingly, in several pathological conditions, including cancer, have been reported a dysregulation in the PTM balance.…”

TRP Channels Regulation of Rho GTPases in Brain Context and Diseases

“…Transient receptor potential channels can be activated by multiple stimuli, such as temperature, pH changes, and membrane mechanical stress ( Clapham, 2003 ). Moreover, the activity of these channels can be modulated by PIP 2 ( Nilius et al, 2008 ; Rohacs, 2014 ), PTMs such as phosphorylation ( Cerda et al, 2015 ; Xu et al, 2019 ; Liu X. et al, 2020 ) and interacting proteins ( Singh et al, 2002 ; Zhu, 2005 ; Cho et al, 2014 ; Rivas et al, 2020 ). Monomers can form heterotetrameric functional channels with distinctive properties in relation with their homotetrameric counterparts ( Chubanov et al, 2004 ; Ma et al, 2011 ; Kim et al, 2019 ).…”