Abstract
Aim: This study aimed to determine the effects of small-conductance Ca2+-activated K+ (SK) channels in colonic relaxation and the regulation of SK channels by estrogen. Methods: The contractile activity of muscle strips from male rats was estimated, and drugs including vehicle (DMSO), 17β-estradiol (E2), or apamin (SK blocker) were added, respectively. In a further experiment, muscle strips were preincubated with apamin before exposure to E2. The levels of the SK2 and SK3 protein expression in the colonic smooth muscle cells (SMCs) were detected. SMCs were treated with ICI 182780 (estrogen receptor [ER] antagonist) plus E2, BSA-E2, PPT (ERα agonist), or DPN (ERβ agonist). SK3 mRNA and protein expression levels were detected. Results: The muscle strips responded to E2 with a decrease and to apamin with a transient increase in tension. Preincubation with apamin partially prevented E2-induced relaxation. Two SK channel subtypes, SK2 and SK3, were coexpressed with α-actin in colonic SMCs. The quantitative ratio of the SK transcriptional expression in colonic SMCs was SK3 > SK2. The SK3 expression was upregulated by E2, and was downregulated by ICI 182780, but was not influenced by BSA-E2. Furthermore, the effect of PPT on the expression of SK3 was almost the same as that of E2, while DPN did not influence the protein expression of SK3. Conclusion: These findings indicate that SK3 is involved in the E2-induced relaxing effect on rat colonic smooth muscle. Furthermore, E2 upregulates the expression of SK3 in rat SMCs, and that this effect is mediated via the ERα receptor.
Journal Section:
Original Paper
References
1.
Arora G, Mannalithara A, Mithal A, Triadafilopoulos G, Singh G: Concurrent conditions in patients with chronic constipation: a population-based study. PLoS One 2012;7:​e42910.
[PubMed]
2.
Longo SA, Moore RC, Canzoneri BJ, Robichaux A: Gastrointestinal conditions during pregnancy. Clin Colon Rectal Surg 2010;23:80-89.
[PubMed]
3.
Oh JE, Kim YW, Park SY, Kim JY: Estrogen rather than progesterone cause constipation in both female and male mice. Korean J Physiol Pharmacol 2013;17:423-426.
[PubMed]
4.
Hogan AM, Kennelly R, Collins D, Baird AW, Winter DC: Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism. Br J Surg 2009;96:817-822.
[PubMed]
5.
Güal O, Bozkurt A, Deniz M, Sungur M, Yeğen BC: Effect of sex steroids on colonic distension-induced delay of gastric emptying in rats. J Gastroenterol Hepatol 2004;19:975-981.
[PubMed]
6.
Garcia-Junco-Clemente P, Chow DK, Tring E, Lazaro MT, Trachtenberg JT, Golshani P: Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism. Proc Natl Acad Sci U S A 2013;110:18297-18302.
[PubMed]
7.
Chen L, Deltheil T, Turle-Lorenzo N, Liberge M, Rosier C, Watabe I, Sreng L, Amalric M, Mourre C: SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats. Int J Neuropsychopharmacol 2014;17:1295-1306.
[PubMed]
8.
Gil V, Gallego D, Moha Ou Maati H, Peyronnet R, Martínez-Cutillas M, Heurteaux C, Borsotto M, Jiménez M: Relative contribution of SKCa and TREK1 channels in purinergic and nitrergic neuromuscular transmission in the rat colon. Am J Physiol Gastrointest Liver Physiol 2012;303:G412-G423.
[PubMed]
9.
Kelly MJ, Rønnekleiv OK, Ibrahim N, Lagrange AH, Wagner EJ: Estrogen modulation of K(+) channel activity in hypothalamic neurons involved in the control of the reproductive axis. Steroids 2002;67:447-456.
[PubMed]
10.
Bosch MA, Kelly MJ, Rønnekleiv OK: Distribution, neuronal colocalization, and 17beta-E2 modulation of small conductance calcium-activated K(+) channel (SK3) mRNA in the guinea pig brain. Endocrinology 2002;143:1097-1107.
[PubMed]
11.
Palmer ML, Schiller KR, O'Grady SM: Apical SK potassium channels and Ca2+-dependent anion secretion in endometrial epithelial cells. J Physiol 2008;586:717-726.
[PubMed]
12.
Pierce SL, England SK: SK3 channel expression during pregnancy is regulated through estrogen and Sp factor-mediated transcriptional control of the KCNN3 gene. Am J Physiol Endocrinol Metab 2010;299:E640-E646.
[PubMed]
13.
Pierce SL, Kresowik JD, Lamping KG, England SK: Overexpression of SK3 channels dampens uterine contractility to prevent preterm labor in mice. Biol Reprod 2008;78:1058-1063.
[PubMed]
14.
Díaz M, Ramírez CM, Marin R, Marrero-Alonso J, Gómez T, Alonso R: Acute relaxation of mouse duodenum [correction of duodenun] by estrogens. Evidence for an estrogen receptor-independent modulation of muscle excitability. Eur J Pharmacol 2004;501:161-178.
[PubMed]
15.
Beckett EA, McCloskey C, O'Kane N, Sanders KM, Koh SD: Effects of female steroid hormones on A-type K+ currents in murine colon. J Physiol 2006;573(Pt 2):453-468.
[PubMed]
16.
Li F, Lin YM, Sarna SK, Shi XZ: Cellular mechanism of mechanotranscription in colonic smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 2012;303:G646-G656.
[PubMed]
17.
Shi XZ, Lin YM, Powell DW, Sarna SK: Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2. Am J Physiol Gastrointest Liver Physiol 2011;300:G99-G108.
[PubMed]
18.
Shi XZ, Pazdrak K, Saada N, Dai B, Palade P, Sarna SK: Negative transcriptional regulation of human colonic smooth muscle Cav1.2 channels by p50 and p65 subunits of nuclear factor-kappaB. Gastroenterology 2005;129:1518-1532.
[PubMed]
19.
Fisher RS, Roberts GS, Grabowski CJ, Cohen S: Inhibition of lower esophageal sphincter circular muscle by female sex hormones. Am J Physiol 1978;234:E243-E247.
[PubMed]
20.
Shimomura A, Ohama T, Hori M, Ozaki H: 17Beta-estradiol induces gastrointestinal motility disorder by decreasing CPI-17 phosphorylation via changes in rho-family G-protein Rnd expression in small intestine. J Vet Med Sci 2009;71:1591-1597.
[PubMed]
21.
Bauer V, Kuriyama H: The nature of non-cholinergic, non-adrenergic transmission in longitudinal and circular muscles of the guinea-pig ileum. J Physiol 1982;322:375-391.
[PubMed]
22.
Bywater RA, Taylor GS: Non-cholinergic excitatory and inhibitory junction potentials in the circular smooth muscle of the guinea-pig ileum. J Physiol 1986;374:153-164.
[PubMed]
23.
Mulè F, Serio R: NANC inhibitory neurotransmission in mouse isolated stomach: involvement of nitric oxide, ATP and vasoactive intestinal polypeptide. Br J Pharmacol 2003;140:431-437.
[PubMed]
24.
Vogalis F, Goyal RK: Activation of small conductance Ca2+-dependent K+ channels By purinergic agonists in smooth muscle cells of the mouse ileum. J Physiol (Lond) 1997;502:497-508.
[PubMed]
25.
Dhaese I, Vanneste G, Sips P, Buys E, Brouckaert P, Lefebvre RA: Involvement of soluble guanylate cyclase alpha(1) and alpha(2), and SK(Ca) channels in NANC relaxation of mouse distal colon. Eur J Pharmacol 2008;589:251-259.
[PubMed]
26.
Ro S, Hatton WJ, Koh SD, Horowitz B: Molecular properties of small-conductance Ca2+-activated K+ channels expressed in murine colonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 2001;281:G964-G973.
[PubMed]
27.
Klemm MF, Lang RJ: Distribution of Ca2+-activated K+ channel (SK2 and SK3) immunoreactivity in intestinal smooth muscles of the guinea-pig. Clin Exp Pharmacol Physiol 2002;29:18-25.
[PubMed]
28.
Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel MC, Tate SN, Trezise DJ: Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum. Naunyn Schmiedebergs Arch Pharmacol 2004;369:602-615.
[PubMed]
29.
Fujita A, Takeuchi T, Jun H, Hata F: Localization of Ca2+-Activated K+ Channel, SK3, in fibroblast-like cells forming gap junctions with smooth muscle cells in the mouse small intestine. J Pharmacol Sci 2003;92:35-42.
[PubMed]
30.
Iino S, Nojyo Y: Immunohistochemical demonstration of c-Kit-negative fibroblast-like cells in murine gastrointestinal musculature. Arch Histol Cytol 2009;72:107-115.
[PubMed]
31.
Vanderwinden JM, Rumessen JJ, de Kerchove d'Exaerde A Jr, Gillard K, Panthier JJ, de Laet MH, Schiffmann SN: Kit-negative fibroblast-like cells expressing SK3, a Ca2+-activated K+ channel, in the gut musculature in health and disease. Cell Tissue Res 2002;310:349-358.
[PubMed]
32.
Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert TR, Rajagopal AV, Bond CT, Periasamy M, Adelman J, Chiamvimonvat N: Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 2009;587:1087-1100.
[PubMed]
33.
Garland CJ: Compromised vascular endothelial cell SK(Ca) activity: a fundamental aspect of hypertension? Br J Pharmacol 2010;160:833-835.
[PubMed]
34.
Kroigaard C, Dalsgaard T, Simonsen U: Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 2010;298:L531-L542.
[PubMed]
35.
Herrera GM, Pozo MJ, Zvara P, Petkov GV, Bond CT, Adelman JP, Nelson MT: Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel. J Physiol 2003;551:893-903.
[PubMed]
36.
Kurahashi M, Zheng H, Dwyer L, Ward SM, Don Koh S, Sanders KM: A functional role for the ‘fibroblast-like cells' in gastrointestinal smooth muscles. J Physiol 2011;589:697-710.
[PubMed]
37.
Roepke TA, Xue C, Bosch MA, Scanlan TS, Kelly MJ, Rønnekleiv OK: Genes associated with membrane-initiated signaling of estrogen and energy homeostasis. Endocrinology 2008;149:6113-6124.
[PubMed]
38.
Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M: Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways. Mol Cell Biol 2004;24:7681-7694.
[PubMed]
39.
Leitman DC, Paruthiyil S, Vivar OI, Saunier EF, Herber CB, Cohen I, Tagliaferri M, Speed TP: Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. Curr Opin Pharmacol 2010;10:629-636.
[PubMed]
40.
Yore MA, Im D, Webb LK, Zhao Y, Chadwick JG Jr, Molenda-Figueira HA, Haidacher SJ, Denner L, Tetel MJ: Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors. Neuroscience 2010;169:1017-1028.
[PubMed]
41.
Delaunay F, Pettersson K, Tujague M, Gustafsson JA: Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol 2000;58:584-590.
[PubMed]
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