Gi‐coupled receptor activation potentiates Piezo2 currents via Gβγ

  • John Smith Del Rosario
    Department of Pharmacology, Physiology and Neuroscience New Jersey Medical School Rutgers, the State University of New Jersey Newark NJ USA
  • Yevgen Yudin
    Department of Pharmacology, Physiology and Neuroscience New Jersey Medical School Rutgers, the State University of New Jersey Newark NJ USA
  • Songxue Su
    Department of Pharmacology, Physiology and Neuroscience New Jersey Medical School Rutgers, the State University of New Jersey Newark NJ USA
  • Cassandra M Hartle
    Department of Molecular and Functional Genomics Weis Center for Research Geisinger Clinic Danville PA USA
  • Tooraj Mirshahi
    Department of Molecular and Functional Genomics Weis Center for Research Geisinger Clinic Danville PA USA
  • Tibor Rohacs
    Department of Pharmacology, Physiology and Neuroscience New Jersey Medical School Rutgers, the State University of New Jersey Newark NJ USA

抄録

<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>

収録刊行物

  • EMBO reports

    EMBO reports 21 (5), 2020-03-29

    Springer Science and Business Media LLC

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