# Structural determinants for GPCR-mediated inhibition of TASK K2P channels by diacylglycerol and its dysfunction in disease

## TL;DR

This study reveals how diacylglycerol inhibits potassium channels through a specific structural site, explaining why this process fails in certain neurodevelopmental disorders.

## Contribution

The study identifies a DAG interaction site in TASK K2P channels and explains the molecular basis for GPCR-mediated inhibition and its dysfunction in disease.

## Key findings

- GPCR inhibition of TASK channels is state-dependent and mediated by DAG binding to a groove formed by M2, M3, and M4 domains.
- Disease-causing mutations in TASK channels disrupt DAG interaction and lead to a common regulatory defect.
- The inhibitory effect of DAG is linked to destabilization of the open state of the channel.

## Abstract

Two-Pore Domain K+ (K2P) channels are crucial determinants of the resting membrane potential and of cellular electrical excitability in many different cell types. TASK-1 and TASK-3 K2P channel activity is also coupled to GPCR signalling pathways via Gαq and their subsequent inhibition is via direct interaction with diacylglycerol (DAG) generated from phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis. This regulation is defective in two different neurodevelopmental disorders, but the molecular mechanisms underlying this inhibitory process and the reasons for the GPCR-insensitivity of these disease-causing mutations remain unclear. Here we show that GqPCR inhibition inversely correlates with channel open probability, and results from a state-dependent destabilisation of the open state by DAG promoting channel closure. We also identify a DAG interaction-site within a groove between the M2, M3 and M4 domains, and show the crucial role of residues within this site in mediating the inhibitory effect and defining channel sensitivity. These results not only reveal the structural and molecular mechanisms underlying GqPCR regulation of TASK channels, but also explain the pathogenic effect of a common regulatory defect linked to different K2P channelopathies.

Gαq-mediated GPCR inhibition of TASK K+ channels depends on the direct binding of PLC-generated diacylglycerol to the channel. This study reveals the structural determinants for this inhibition and explains why this mechanism becomes defective in neurodevelopmental disorders linked to pathogenic mutations in TASK K2P channels.

Gαq-mediated GPCR inhibition is state-dependent, and DAG efficacy decreases with increasing channel open-probability.DAG interacts with an external groove formed by the M2, M3 & M4 helices to destabilise the open state.Disease-causing ‘gain-of-function’ mutations all exhibit a common regulatory defect linked to their change in single channel activity.

Gαq-mediated GPCR inhibition is state-dependent, and DAG efficacy decreases with increasing channel open-probability.

DAG interacts with an external groove formed by the M2, M3 & M4 helices to destabilise the open state.

Disease-causing ‘gain-of-function’ mutations all exhibit a common regulatory defect linked to their change in single channel activity.

Potassium leak channels are inhibited through direct, state-dependent binding of diacylglycerol, a mechanism disrupted in disease.