Gi‐coupled receptor activation potentiates Piezo2 currents via Gβγ

<jats:title>Abstract</jats:title><jats:p>Mechanically activated Piezo2 channels are key players in somatosensory touch, but their regulation by cellular signaling pathways is poorly understood. Dorsal root ganglion (<jats:styled-content style="fixed-case">DRG</jats:styled-content>) neurons express a variety of G‐protein‐coupled receptors that modulate the function of sensory ion channels. Gi‐coupled receptors are generally considered inhibitory, as they usually decrease excitability. Paradoxically, activation of Gi‐coupled receptors in <jats:styled-content style="fixed-case">DRG</jats:styled-content> neurons sometimes induces mechanical hypersensitivity, the mechanism of which is not well understood. Here, we find that activation of Gi‐coupled receptors potentiates mechanically activated currents in <jats:styled-content style="fixed-case">DRG</jats:styled-content> neurons and heterologously expressed Piezo2 channels, but inhibits Piezo1 currents in heterologous systems in a Gβγ‐dependent manner. Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3‐kinase (<jats:styled-content style="fixed-case">PI</jats:styled-content>3K) and mitogen‐activated protein kinase (<jats:styled-content style="fixed-case">MAPK</jats:styled-content>) also abolishes the potentiation of Piezo2 currents. Local injection of sumatriptan, an agonist of the Gi‐coupled serotonin 1B/1D receptors, increases mechanical sensitivity in mice, and the effect is abolished by inhibiting <jats:styled-content style="fixed-case">PI</jats:styled-content>3K and <jats:styled-content style="fixed-case">MAPK</jats:styled-content>. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents and alter mechanosensitivity after activation of Gi‐coupled receptors.</jats:p>