SK3 (small conductance calcium-activated potassium channel 3) also known as K<sub>Ca</sub>2.3 is a protein that in humans is encoded by the KCNN3 gene.
SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current (I<sub>AHP</sub>). It belongs to a family of channels known as small-conductance potassium channels, which consists of three members â SK1, SK2 and SK3 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity. These channels have acquired a number of alternative names, however a NC-IUPHAR has recently achieved consensus on the best names, K<sub>Ca</sub>2.1 (SK1), K<sub>Ca</sub>2.2 (SK2) and K<sub>Ca</sub>2.3 (SK3). Small conductance channels are responsible for the medium and possibly the slow components of the I<sub>AHP</sub>.
K<sub>Ca</sub>2.3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini and is readily blocked by apamin. The gene for K<sub>Ca</sub>2.3, KCNN3, is located on chromosome 1q21.
K<sub>Ca</sub>2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues. K<sub>Ca</sub>2.3 is most abundant in regions of the brain, but has also been found to be expressed in significant levels in many other peripheral tissues, particularly those rich in smooth muscle, including the rectum, corpus cavernosum, colon, small intestine and myometrium.
The expression level of KCNN3 is dependent on hormonal regulation, particularly by the sex hormone estrogen. Estrogen not only enhances transcription of the KCNN3 gene, but also affects the activity of K<sub>Ca</sub>2.3 channels on the cell membrane. In GABAergic preoptic area neurons, estrogen enhanced the ability of ñ1 adrenergic receptors to inhibit K<sub>Ca</sub>2.3 activity, increasing cell excitability. Links have been established between hormonal regulation of sex-organ function and K<sub>Ca</sub>2.3 expression. The expression of K<sub>Ca</sub>2.3 in the corpus cavernosum in patients undergoing estrogen treatment as part of gender-reassignment surgery was found to be increased up to 5-fold. The influence of estrogen on K<sub>Ca</sub>2.3 has also been established in the hypothalamus and in uterine and skeletal muscle.
K<sub>Ca</sub>2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of K<sub>Ca</sub>2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of K<sub>Ca</sub>2.3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions. Blocking the K<sub>Ca</sub>2.3 channel or suppressing K<sub>Ca</sub>2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure.
Mutations in K<sub>Ca</sub>2.3 are suspected to be a possible underlying cause for several neurological disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, anorexia nervosa and ataxia as well as myotonic muscular dystrophy.