| Autor: |
Del Rosario, John Smith, Yudin, Yevgen, Su, Songxue, Hartle, Cassandra M, Mirshahi, Tooraj, Rohacs, Tibor |
| Zdroj: |
EMBO Reports; 5/6/2020, Vol. 21 Issue 5, p1-12, 12p |
| Abstrakt: |
Mechanically activated Piezo2 channels are key players in somatosensory touch, but their regulation by cellular signaling pathways is poorly understood. Dorsal root ganglion (DRG) 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 DRG 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 DRG 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 (PI3K) and mitogen‐activated protein kinase (MAPK) 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 PI3K and MAPK. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents and alter mechanosensitivity after activation of Gi‐coupled receptors. Synopsis: Activation of inhibitory Gi‐coupled receptors potentiates the activity of the mechanosensitive ion channel Piezo2 through Gβγ and downstream protein kinases. This effect may contribute to the mechanical hyperalgesia induced by Gi‐coupled receptor activation. Activation of Gi‐coupled receptors potentiates Piezo2 and inhibits Piezo1 channel activity through Gβγ.Piezo2 current potentiation depends on downstream PI3‐Kinase and MAP‐Kinase enzymes.Local injection of sumatriptan, a serotonin 1D/1B receptor agonist, increases mechanical sensitivity in behavioral experiments in a PI3K and MAPK dependent manner in mice. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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