Gi-coupled receptor activation potentiates Piezo2 currents via Gβγ

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Signaling

Background:

• Mechanically activated Piezo2 channels are crucial for somatosensory touch perception.
• Regulation of Piezo2 channels by cellular signaling pathways, particularly G-protein-coupled receptors (GPCRs), is not well understood.
• Gi-coupled receptors are typically inhibitory, yet paradoxically can induce mechanical hypersensitivity in dorsal root ganglion (DRG) neurons.

Purpose of the Study:

• To elucidate the mechanism by which Gi-coupled receptors modulate Piezo2 channel function.
• To investigate the role of Gβγ subunits and downstream kinases in this modulation.
• To determine the in vivo relevance of this pathway in mechanical sensitivity.

Main Methods:

• Electrophysiological recordings of mechanically activated currents in DRG neurons and heterologously expressed Piezo2 and Piezo1 channels.
• Pharmacological inhibition of Gβγ-dependent kinases, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK).
• In vivo assessment of mechanical sensitivity in mice following administration of a Gi-coupled receptor agonist (sumatriptan) and kinase inhibitors.

Main Results:

• Activation of Gi-coupled receptors potentiated Piezo2 currents in DRG neurons and heterologous systems, but inhibited Piezo1 currents.
• This potentiation was dependent on Gβγ subunits and abolished by inhibiting PI3K and MAPK.
• In vivo, sumatriptan administration increased mechanical sensitivity in mice, an effect abrogated by PI3K and MAPK inhibition.

Conclusions:

• Gi-coupled receptor activation indirectly sensitizes Piezo2 channels via Gβγ subunits and downstream PI3K/MAPK signaling.
• This pathway provides a novel mechanism explaining how Gi-coupled receptors can paradoxically enhance mechanical sensitivity.
• The findings highlight a new regulatory mechanism for mechanotransduction and pain perception.