Abstract
The study of the structure–function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure–function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure–relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms.
Highlights
Transient receptor potential canonical (TRPC) channels constitute non-selective, Ca2+ -permeable channels in mammalian cells [1,2,3]
It is worthy to remark that mutation to D633N changed I-V shape but critically diminished absolute amount of inward current through the channel. These results have suggested that the aspartate residue is crucial for crucial for magnesium binding and inward-rectification, and the stabilization of the residue by electrostatic interaction with Mg2+ seems to be necessary for the channel to elicit inward cationic current
Using the voltage-sensitive phosphatase (VSP) system, the study has shown that the Englerin-A-activated current of TRPC4α, TRPC4β and TRPC5 channels were all inhibited by activation of VSP by depolarized pulse sequence
Summary
Transient receptor potential canonical (TRPC) channels constitute non-selective, Ca2+ -permeable channels in mammalian cells [1,2,3]. TRPC4 and 5, show somewhat localized expression profile such as brain [7,8,9,10,11,12,13,14,15,16,17,18], gastrointestinal tract (GI tract) [2,3,19,20,21,22], ovary [23,24], endometrium [25,26], ventricular myocytes [27,28,29], and vasculature [30,31,32,33] In such tissues, TRPC 1, 4, and 5 channels are known to modulate fear or stress response, integrity of dopaminergic motor neurons such as substantia nigra, hypertrophic cardiomyopathy, endothelial dysfunction, cholinergic contraction of GI smooth muscle, and many others. We presume that such questions should be answered in order to fully understand TRPC4, 5, and related heterotetrameric channels (TRPC1/4 and TRPC1/5)
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