Kir3x

Kir3x refers to the subfamily of inwardly rectifying potassium channels known as GIRK (G protein-gated inwardly rectifying potassium) channels. They are a subset of the Kir channel family and form functional channels as tetramers composed of Kir3.1–Kir3.4 subunits. Subunits can assemble into homo- or heterotetramers, which have distinct regulatory and pharmacological properties. Kir3x channels are highly expressed in the brain and heart, where they contribute to setting resting membrane potential and modulating cellular excitability.

Activation of Kir3x channels occurs when Gβγ subunits, released from Gi/o-coupled G protein–coupled receptors, bind to the channel. They are typically activated downstream of receptors such as muscarinic M2 in the heart and various neurotransmitter receptors in the brain. Channel opening increases K+ conductance, leading to hyperpolarization and a reduction in neuronal or cardiac excitability. In cardiac tissue, Kir3.x channels contribute to the acetylcholine-activated IKACh current, helping regulate heart rate and atrial electrical activity.

Structure and regulation: Each Kir3x subunit has two transmembrane domains (M1 and M2) with cytoplasmic N- and C-termini that provide sites for regulation and subunit assembly. Channel activity is modulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and is sensitive to intracellular magnesium and polyamines, which contribute to their characteristic inward rectification. Pharmacological blockers include peptide toxins such as tertiapin, and several selective modulators have been investigated for research and therapeutic potential.

Physiological and clinical relevance: Kir3x channels regulate neuronal signaling, synaptic integration, and cardiac rhythm. Altered GIRK channel function has been implicated in neurological disorders, cardiac arrhythmias, and certain pain pathways, making them a focus of pharmacological research.