The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels

TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by mu-opioid receptors through the signaling of G beta gamma proteins, thereby reducing TRPM3-mediated pain. We show here that G beta gamma directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with G beta gamma. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in G beta 1 that are indi-vidually necessary for TRPM3 inhibition by G beta gamma. The 10-amino-acid G beta gamma-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that G beta gamma proteins exert on TRPM3 channels.