SK3

SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent afterhyperpolarisation current (I_AHP). 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 (Chen et al 2004). Small conductance channels are responsible for the medium and possibly the slow components of the I_AHP.

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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 α1 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 up to 5-fold (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).

References

• Chen, M.X, Gorman S, Benson B, Singh K, Hieble J.P, Michel M, Tate S, Trezise D. 2004. Small and intermediate conductance Ca2+ activated K+ channels confer distinctive patterns of distbribution in human tissues and differential cellular localisation in the colon and corpus cavernosum. Naunyn-Schmiedeberg’s Arch Pharmacol. 369:602-615

• Hamilton, K. 2007. Physiological Aspects of Health and Disease K+ Channelopathies Practical Experimental Protocol. University Press, Dunedin, NZ.

• Jacobson D, Pribnow D, Herson PS, Maylie J, Adelman JP. 2003. Determinants contributing to estrogen-regulated expression of SK3. Biochemical and Biophysical Research Communications 303:600-608

• Kimura T, Takahashi MP, Fujimura H, Sakoda S. 2003. Expression and distribution of a small-conductance calcium-activated potassium channel (SK3) protein in skeletal muscles from myotonic muscular dystrophy patients and congenital myotonic mice. Neuroscience Letters 347(3):191-5

• Kohler M, Hirschberg B, Band CT, Kinie JM, Marrion NV, Maylie J, Adelman JP. 1996. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273:1709-1714

• Koronyo-Hamaoui M, Frisch A, Stein D, Denziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Ram A, Zubery E, Jeczmien P, Apter A, Weizman A, Gak E. 2007. Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa. J Psychiatr Res 41(1-2):160-7

• Koronyo-Hamaoui M, Gak E, Stein D, Frisch A, Danziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Apter A, Goldman B, Barkai G, Weizman A. 2004. CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population. Am J Med Genet B Neuropsychiatr Genet 131(1):76-80

• Taylor M, Bonev A, Gross TP, Eckman DM, Brayden J, Bond C, Adelman JP, Nelson MT. 2003. Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circulation Research 93:124-131

• Tomita H, Shakkottai VG, Gutman GA, Sun G, Bunney WE, Cahalan MD, Chandy KG, Garjus JJ. 2003. Novel truncated isoform of SK3 potassium channel is a potent dominant-negative reguator of SK currents: implications in schizophrenia. Molecular psychiatry 8:524-535

• Wolfart J, Neuhoff H, Franz O, Roeper J. 2001. Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. Journal of Neuroscience 21(10):3443-3456