Influence of membrane cholesterol in the molecular evolution and functional regulation of TRPV4

TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulator

“…Recent reports also suggest that MAM regions are relevant for several neurological disorders, as mitochondrial functions are related with critical functions, such as lipid homeostasis, cholesterol biogenesis, mitochondrial calcium signalling, mitochondrial morphology and mitochondrial dynamics (Krols et al, 2016). Our previous study demonstrated that TRPV4 has ability to interact with different sterols, sterolprecursors and their derivatives (Kumari et al 2015). These findings support the notion that presence of TRPV4 in the MAM can be of functional importance for sterol transport between ER and mitochondria (Kumari et al 2015).…”

Cholesterol regulates polymodal sensory transduction in Müller glia

“…Block of stretch-activated and TRPV1 channels by Grammostola spatulata (GsMtx4) and Ornithoctonus huwena (DkTx) venoms has been similarly attributed to the ability of toxins to partition into the lipid membrane and stabilize the open pore (Gao et al, 2016;Suchyna et al, 2004). However, vanilloid TRPs may also be regulated through conserved cholesterol-binding CRAC (Cholesterol Recognition/Interaction Amino acid Consensus) domains that span the loop between TM4 and TM5 (amino acids 576 -632) of TRPV4 (Kumari et al, 2015) and CARC domains that mediate cholesterol binding in cognate TRPV1 (Picazo-Ju arez et al, 2011). CARC-containing TRPV1 and inwardly rectifying Kir3.1/Kir3.4 (GIRK) channels are inhibited by MbCD (Bukiya, Durdagi, Noskov, & Rosenhouse-Dantsker, 2017;Liu, Huang, Wu, & Priestley, 2006;Szoke et al, 2010) whereas cholesterol increases the open probability but not the unitary conductance of GIRK channels that subserve cardiac K ACh currents (Bukiya et al, 2015).…”

“…Given that TRPV4 is activated by many types of membrane-delimited events that include swelling, pressure, pulling and mechanical displacement (Jo et al, 2015;Matthews et al, 2010;Rocio Servin-Vences et al, 2017) and that its molecular structure-function may have co-evolved with key enzymes in cholesterol biosynthesis (Kumari et al, 2015), we asked whether the activation of TRPV4 might be influenced by the levels of membrane cholesterol. M€ uller cells were incubated with MbCD for 1 hr to deplete their cholesterol levels (Figure 1), and exposed to the selective TRPV4 agonist GSK1016780A (GSK101) at its approximate EC 50 (25 nM) (Ryskamp et al, 2014).…”

Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data

“…[8][9][10] In agreement with these reports, recent studies have indeed confirmed that different domains and motifs of TRP channels had undergone differential selection pressure throughout vertebrate evolution. 3,5,11 This leads to changes in the sequence of TRP channels, especially in certain key regions affecting its structure -function relationship, which is either beneficial (thus selected) or may become deleterious (thus not selected) during molecular evolution.…”

“…4 Similarly, Amphibians have probably achieved high sensitivity by multiplying TRPV4 gene several times. 5 African Naked mole rats (Heterocephalus glaber) have a very high acid tolerance, which can be explained by their unique properties of nociceptors that express TRPV1 with various point mutations. 6 Chickens as well as almost all birds show very low sensitivity toward Capsaicin (till 100 mM) and no detectable binding of Resiniferatoxin due to a point mutation (S512Y) making the avian TRPV1 insensitive to these noxious compounds.…”