Dataset Information

Dual action of the G?_q-PLC?-PI(4,5)P₂ pathway on TRPC1/4 and TRPC1/5 heterotetramers.

ABSTRACT: The transient receptor potential canonical (TRPC) 1 channel is widely distributed in mammalian cells and is involved in many physiological processes. TRPC1 is primarily considered a regulatory subunit that forms heterotetrameric channels with either TRPC4 or TRPC5 subunits. Here, we suggest that the regulation of TRPC1/4 and TRPC1/5 heterotetrameric channels by the G?_q-PLC? pathway is self-limited and dynamically mediated by G?_q and PI(4,5)P₂. We provide evidence indicating that G?_q protein directly interacts with either TRPC4 or TRPC5 of the heterotetrameric channels to permit activation. Simultaneously, G?_q-coupled PLC? activation leads to the breakdown of PI(4,5)P₂, which inhibits activity of TRPC1/4 and 1/5 channels.

SUBMITTER: Myeong J

PROVIDER: S-EPMC6092394 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Dual action of the Gαq-PLCβ-PI(4,5)P2 pathway on TRPC1/4 and TRPC1/5 heterotetramers.

Myeong Jongyun J Ko Juyeon J Kwak Misun M Kim Jinsung J Woo Joohan J Ha Kotdaji K Hong Chansik C Yang Dongki D Kim Hyun Jin HJ Jeon Ju-Hong JH So Insuk I

Scientific reports 20180814 1

The transient receptor potential canonical (TRPC) 1 channel is widely distributed in mammalian cells and is involved in many physiological processes. TRPC1 is primarily considered a regulatory subunit that forms heterotetrameric channels with either TRPC4 or TRPC5 subunits. Here, we suggest that the regulation of TRPC1/4 and TRPC1/5 heterotetrameric channels by the Gαq-PLCβ pathway is self-limited and dynamically mediated by Gαq and PI(4,5)P2. We provide evidence ...[more]

PMID: 30108272

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Project description:Transient receptor potential classical (or canonical) (TRPC)3, TRPC6, and TRPC7 are a subfamily of TRPC channels activated by diacylglycerol (DAG) produced through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) by phospholipase C (PLC). PI(4,5)P2 depletion by a heterologously expressed phosphatase inhibits TRPC3, TRPC6, and TRPC7 activity independently of DAG; however, the physiological role of PI(4,5)P2 reduction on channel activity remains unclear. We used Förster resonance energy transfer (FRET) to measure PI(4,5)P2 or DAG dynamics concurrently with TRPC6 or TRPC7 currents after agonist stimulation of receptors that couple to Gq and thereby activate PLC. Measurements made at different levels of receptor activation revealed a correlation between the kinetics of PI(4,5)P2 reduction and those of receptor-operated TRPC6 and TRPC7 current activation and inactivation. In contrast, DAG production correlated with channel activation but not inactivation; moreover, the time course of channel inactivation was unchanged in protein kinase C-insensitive mutants. These results suggest that inactivation of receptor-operated TRPC currents is primarily mediated by the dissociation of PI(4,5)P2. We determined the functional dissociation constant of PI(4,5)P2 to TRPC channels using FRET of the PLC? Pleckstrin homology domain (PHd), which binds PI(4,5)P2, and used this constant to fit our experimental data to a model in which channel gating is controlled by PI(4,5)P2 and DAG. This model predicted similar FRET dynamics of the PHd to measured FRET in either human embryonic kidney cells or smooth muscle cells, whereas a model lacking PI(4,5)P2 regulation failed to reproduce the experimental data, confirming the inhibitory role of PI(4,5)P2 depletion on TRPC currents. Our model also explains various PLC-dependent characteristics of channel activity, including limitation of maximum open probability, shortening of the peak time, and the bell-shaped response of total current. In conclusion, our studies demonstrate a fundamental role for PI(4,5)P2 in regulating TRPC6 and TRPC7 activity triggered by PLC-coupled receptor stimulation.

Dataset Information

Dual action of the G?_q-PLC?-PI(4,5)P₂ pathway on TRPC1/4 and TRPC1/5 heterotetramers.

Publications

Dual action of the Gα<sub>q</sub>-PLCβ-PI(4,5)P<sub>2</sub> pathway on TRPC1/4 and TRPC1/5 heterotetramers.

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Dataset Information

Dual action of the G?q-PLC?-PI(4,5)P2 pathway on TRPC1/4 and TRPC1/5 heterotetramers.

Publications

Dual action of the Gα<sub>q</sub>-PLCβ-PI(4,5)P<sub>2</sub> pathway on TRPC1/4 and TRPC1/5 heterotetramers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dual action of the G?_q-PLC?-PI(4,5)P₂ pathway on TRPC1/4 and TRPC1/5 heterotetramers.