G protein-dependent signaling pathways control the activity of excitable cells of the nervous system and heart, and are the targets of neurotransmitters, clinically relevant drugs, and drugs of abuse. G protein-gated inwardly rectifying potassium (K+) (Girk/Kir3) channels are a key effector in inhibitory signaling pathways. Girk-dependent signaling contributes to nociception and analgesia, reward-related behavior, mood, cognition, and heart-rate regulation, and has been linked to epilepsy, Down syndrome, addiction, and arrhythmias. We discuss recent advances in our understanding of Girk channel structure, organization in signaling complexes, and plasticity, as well as progress on the development of subunit-selective Girk modulators. These findings offer new hope for the selective manipulation of Girk channels to treat a variety of debilitating afflictions.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH) grants to K.W. (MH061933, HL105550, and DA034696) and by the Spanish Ministry of Science and Innovation BFU2012-38348 and CONSOLIDER-Ingenio CSD2008-0000 (to R.L.). The authors thank members of the Wickman and Luján laboratories for their suggestions for the manuscript.