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. 2020 Oct:17:25-33.
doi: 10.1016/j.cophys.2020.06.005. Epub 2020 Jun 29.

Mechanisms and significance of Ca2+ entry through TRPC channels

Bernadett Bacsa  1 , Oleksandra Tiapko  1 , Thomas Stockner  2 , Klaus Groschner  1
Affiliations

Mechanisms and significance of Ca2+ entry through TRPC channels

Bernadett Bacsa et al. Curr Opin Physiol. 2020 Oct.

Abstract

The transient receptor potential (TRP) superfamily of plasma membrane cation channels has been recognized as a signaling hub in highly diverse settings of human physiopathology. In the past three decades of TRP research, attention was focused mainly on the channels Ca2+ signaling function, albeit additional cellular functions, aside of providing a Ca2+ entry pathway, have been identified. Our understanding of Ca2+ signaling by TRP proteins has recently been advanced by a gain in high-resolution structure information on these pore complexes, and by the development of novel tools to investigate their role in spatiotemporal Ca2+ handling. This review summarizes recent discoveries as well as remaining, unresolved aspects of the canonical subfamily of transient receptor potential channels (TRPC) research. We aim at a concise overview on current mechanistic concepts of Ca2+ entry through- and Ca2+ signaling by TRPC channels.

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Conflict of interest statement

Conflict of interest statement Nothing declared.

Figures

Figure 1
Figure 1. Molecular architecture of the TRPC Ca2+ permeation pathway.
(a) Pore structure of homology modelled TRPC1 (based on mTRPC4 with PDB ID: 5Z96 [42] and TRPC7 (using the hTRPC3 with the PDB ID: 6CUD as template [44] and cryoEM structures of TRPCs (hTRPC3 PDB ID: 5ZBG [40]; hTRPC4 PDB ID: 5Z96 [42]; mTRPC5 PDB ID: 6AEI; hTRPC6 PDB ID: 5YX9 [40]. Divalent ion recognition site (red; blue in TRPC1), the most constricted regions of selectivity filter (green) and lower gate (pink; blue in TRPC1) are highlighted. (b) Sequence alignment of TRPCs according to Fan et al. [44]. Divalent recognition site, most restricted region of the selectivity filter (green) and lower gate (pink; blue in TRPC1) are highlighted. Other important residues within the pore structure according to cryoEM and experimental data are highlighted bold.
Figure 2
Figure 2
(a) Molecular and mechanistic determinants of TRPC Ca2+ signaling: Efficient and specific signal transduction requires Ca2+ permeation as well as assembly of TRPC tetramers within signalplexes as well as membrane microdomains. Ca2+ signaling involves control of amplitude but also kinetics of TRPC-mediated Ca2+ changes as well as positioning of downstream Ca2+ sensors within an adequate distance to the Ca2+ source. This requires a multitude of signaling partners including scaffolds and adaptor molecules, signal amplifiers and downstream targets. (b) Heterogenity of the molecular organization in TRPC-centered Ca2+ signaling microdomains: TRPC channels interact with scaffolding proteins for plasma membrane targeting and for incorporation in signalplex components that determine channel activity, clustering, signal amplification and anchoring of downstream targets. TRPC1 of secretory cells interacts with Caveolin-1 (Cav-1) in cholesterol-rich vesicles and lipid rafts/caveolae [11,15] thereby rendering the channels rather inactive. Upon ER-store depletion, STIM1 translocates to ER-PM junctions activates Orai1 channels. Orai1-induced SOCE recruits TRPC1 into these junctional regions reducing the pool of TRPC1 associated with Cav-1 and allowing its activation by STIM1. TRPC1 proposedly interacts also with CaM/IP3R in mutually exclusive manner within such ER-PM contact sites. TRPC4/5 channels assemble with NHERF, which anchors the channel via ezrin to the actin cytoskeleton, thereby imparting phosphorylation-dependent control over lipid gating, specifically on its interaction with DAG. TRPC4/5 channels as well as TRPC3/6 channels generate a Ca2+ microdomain, which impacts on the PM lipid environment via PLSCR1. This scramblase, like other downstream Ca2+ sensors such as calmodulin (CaM) and calcineurin (CaN), is reportedly activated within the channels vicinity, where it might physically be anchored to TRPCs [ *] and in some cells is reportedly controlled by translation of Na+ influx through TRPCs into local Ca2+ rises by the signal amplifier NCX1 [64].
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