Abstract
Transient receptor potential (TRP) channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human. TRP channels exert a multitude of physiological functions ranging from Ca2+ homeostasis in the kidney to pain reception and vision. These channels are activated by a wide range of stimuli and undergo covalent post-translational modifications that affect and modulate their subcellular targeting, their biophysical properties, or channel gating. These modifications include N-linked glycosylation, protein phosphorylation, and covalent attachment of chemicals that reversibly bind to specific cysteine residues. The latter modification represents an unusual activation mechanism of ligand-gated ion channels that is in contrast to the lock-and-key paradigm of receptor activation by its agonists. In this review, we summarize the post-translational modifications identified on TRP channels and, when available, explain their physiological role.
Highlights
Transient receptor potential (TRP) channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human
The members of the canonical TRP receptor subfamily, TRPC3, TRPC6, and TRPC7, are activated by the permeant diacyl glycerol (DAG) analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG) and this activation is reversed by the PKC activator 12-myristate 13-acetate (PMA) [19,79,80,81]
The moonwalker mouse mutant exhibits cerebellar ataxia and abnormal Purkinje cell development [14]. This phenotype is caused by a point mutation of Thr635 (Thr646 in human TRPC3) that results in reduced PKC-mediated phosphorylation of TRPC3 in moonwalker mice
Summary
The first transient receptor potential (TRP) channel was uncovered in the compound eye of Drosophila melanogaster. The Drosophila TRP channel belongs to the subfamily of TRPC (canonical) channels. The structure of TRPV1 has been resolved to 3.4 Å resolution by single particle cryo-electron microscopy [5,6] These studies revealed a channel pore with a dual gating mechanism composed of a selectivity filter formed by the S5-S6 pore loop, that is located near the outer surface of the channel, and a second lower gate formed by parts of the S6 helix. Activation of TRP channels can either occur via a receptor and a signaling cascade that culminates in the opening of the channel, which is the canonical activation mechanism for TRPC channels, or the channel itself is a receptor as exemplified by TRPV1
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