SK3

SK3 is a small-conductance calcium activated K+ channel partly responsible for the calcium-dependent after-hyperpolarisation current (IAHP). It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – Sk1, Sk2 and Sk3 (KCNN1, 2 and 3 respectively), which share a 60-70% sequence identity among them (Chen et al 2004). Small conductance channels are responsible for the medium and possibly the slow components of the IAHP

Structure
SK3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini. (Kohler et al 1996, Chen et al 2004), and is readily blocked by apamin. The gene for SK3 is located on chromosome 1q21.

Expression
SK3 is found in almost every tissue in the human body, with exceptions being the pancreas, placenta, adipose tissue, liver, prostate and skin (Chen et al, 2004). SK3 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 myometirum (Chen et al 2004).

The expression level of SK3 is dependent on hormonal regulation, particularly by the sex hormone estrogen. Estrogen not only enhances transcription of the SK3 gene, but also affects the activity of SK3 channels on the cell membrane. In GABAergic POA neurons, estrogen enhanced the ability of a-1 adrenergic receptors to inhibit SK3 activity, increasing cell excitability (Jacobson et al 2003). Links between hormonal regulation of sex organ function and SK3 expression have been established. The expression of SK3 in the corpus cavernosum in patients undergoing estrogen treatment as part of gender reassignment surgery was found to be increased by up to 5 times (Chen et al 2004). The influence of estrogen on SK3 has also been established in the hypothalamus, uterine and skeletal muscle (Jacobson et al 2003).

Physiology
SK3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of SK3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of SK3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions (Taylor et al 2003). Blocking the SK3 channel or suppressing SK3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure.

Pathology
Mutations in SK3 are suspected to be a possible underlying cause for several neurological disorders, including schizophrenia, bipolar disorder, Alzheimer’s disease, anorexia nervosa and ataxia (Koronyo-Hamaoui et al 2007, Koronyo-Hamaoui et al 2004, Tomita et al 2003), as well as myotonic muscular dystrophy (Kimura et al 2003).