Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

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Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

Christian Lscher* and Paul A. Slesinger||

Abstract | G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to activation of many different G protein-coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on the channel subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death, which may be important in the pathophysiology of diseases such as epilepsy, Downs syndrome, Parkinsons disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target.

*Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1 Michel Servet, CH1211 Geneva, Switzerland.

Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH1211 Geneva, Switzerland.

Geneva Neuroscience Center, 1 Michel Servet,1211 Geneva, Switzerland.

Peptide Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. emails: mailto:[email protected]

Web End [email protected] ; mailto:[email protected]

Web End [email protected] doi:10.1038/nrn2834 Published online14 April 2010

Much of the interplay between excitatory and inhibitory signals that are required for normal neuronal function occurs in the dendrites of neurons1. Detailed electron and light microscopic studies show that fast excitatory inputs are mediated by ionotropic glutamate receptors such as NMDARs (N-methyl-d-aspartate receptors) and AMPARs (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), located in the postsynaptic density at the head of the spine. By contrast, inhibitory synapses typically form on the soma and dendritic shafts1. The fast inhibitory signals are mediated by ionotropic GABAA (-aminobutyric acid type A) and glycine receptors. In addition to this fast inhibition, a slow inhibitory postsynaptic current (sIPSC) exists that is mediated by G protein-activated inwardly rectifying K+ (GIRK; also known as Kir3) channels that are located perisynaptically outside the postsynaptic density in the spine and on the shaft2. This Review discusses recent findings on the physiology, function and dysfunction of GIRK channels in the brain.

Physiology of GIRK channels

GIRK channels are members of a large family of...