K_ir3.3 (or G-protein regulated Inward-Rectifier K⁺ channel, GIRK3) is a member of the family of inward rectifying K⁺ channels. The family includes 15 members that are structurally and functionally different from the voltage-dependent K⁺ channels.

The family’s topology consists of two transmembrane domains that flank a single and highly conserved pore region with intracellular N- and C-termini. As is the case for the voltage-dependent K+ channels the functional unit for the K_ir channels is composed of four subunit that can assembly as either homo or heterotetramers.

K_ir channels are characterized by a K⁺ efflux that is limited by depolarizing membrane potentials thus making them essential for controlling resting membrane potential and K⁺ homeostasis.

K_ir3.3 is a member of the K_ir3.x subfamily that includes four members (K_ir3.1- K_ir3.4). The K_ir3 family is characterized by the fact that the channels can be activated by neurotransmitters and other factors acting via the activation of G-protein coupled receptors. Binding of the corresponding ligand to the G-protein receptor induces the dissociation of Ga-GTP from the Gbg dimer. The latter directly binds to K_ir3 and activates the channel.^1,2

K_ir3.3 is mainly expressed in the brain, were it co-assembles with K_ir3.1 or K_ir3.2. The functional impact of K_ir3.3 is less well understood than the other K_ir3 channels. However, heteromers composed of K_ir3.2 and K_ir3.3 were found to be primarily responsible for the opioid-induced current and hyperpolarization observed in mouse locus ceruleus (LC) neurons.³