Skip to main content
PMC home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;10(2):280–291. doi: 10.1111/j.1582-4934.2006.tb00399.x

Interstitial cells of Cajal in the urethra

G P Sergeant 1,*, K D Thornbury 1, N G McHale 1, M A Hollywood 1
PMCID: PMC3933121  PMID: 16796799

Abstract

The smooth muscle layer of the urethra generates spontaneous mayogenic tone that is thougth to make a major contibution to urinary continence. The mechanisms underlying generion of tone remin unclear, however recent studies from our laboratory highlighted a role for a specialised population of pacemake cells which we originally referrd ot as interstitil cells (IC) and now term ICC. Urethra ICC possess an electrical pacemaker mechanism charactriesd by rhythmic activation of Ca2+-activated C1- Channels leading to spotaneous transient inward currents (STICs) under voltage clamp and spontaneous transient deplarisations (STDs) under surrent clamp conditons. Both STICS and STDs are now known to be associated with spntaneous Ca2+ under current clamp conditons. Both STIC and STDs are now known to be associated with spontaneius Ca2+ oscillations that result from a complex interplay between releas fo Ca2+ from intracellular stores and Ca2+ influx acrosss the plasma membrane. Ink this review we will consider some of the precise mechanisms involved in the generation of paccemake activity and discuss how these are modulated by excitatory and inhibitory neurotrnsmiters.

Keywords: urethra, smooth Muscle, pacemaker, interstitial cells of Cajal, Calcium oscillations

References

  • 1.Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells. Adv Anat Embryol Cell Biol. 1982;71:1–130. [PubMed] [Google Scholar]
  • 2.Sanders KM. A Case for interstitial cells of Cajal as pacemakers and mediators of neurotransmossinon the gastrointestinal tract. Gastrenterology. 1996;111:492–515. doi: 10.1053/gast.1996.v111.pm8690216. [DOI] [PubMed] [Google Scholar]
  • 3.Huizina JD. Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside. II. Gastric motility: Iesons from Mutant mice on waves and innervation. Am J Physiol Gastrointes Liver Physiol. 2001;281:G1129–34. doi: 10.1152/ajpgi.2001.281.5.G1129. [DOI] [PubMed] [Google Scholar]
  • 4.Huizinga JD, Golden CM, Zhu Y, Hite EJ. Ion Channels in interstitial cells of Cajal as targets for neurotransmitter action. Neurogastroenterol Mitil. 2004;16:106–11. doi: 10.1111/j.1743-3150.2004.00484.x. [DOI] [PubMed] [Google Scholar]
  • 5.Sanders KM, Koh SD, Ward SM. Inerstitial cells of Cajal as pacemakers in the gastrointerstinal trat. Annu Revphysiol. 2006;68:307–43. doi: 10.1146/annurev.physiol.68.040504.094718. [DOI] [PubMed] [Google Scholar]
  • 6.Dickens EJ, Hirst GD, Tomita T. Identification of rthythmically active cells in guinea-pig stopmach. J Physil. 1999;514:515–31. doi: 10.1111/j.1469-7793.1999.515ae.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Smirnov SV, Aaronson PI. Ca2+ currentsin single myocytes from human mesenteric arteries: evidence for a phyisological role of L-type channels. J Physiol. 1992;457:455–75. doi: 10.1113/jphysiol.1992.sp019387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Fleischmann BK, Murray RD, Kotlikoff MI. Voltage window for sustained elevaton of cytosolic calcium in smoot muscle cells. Proc Natl Acad Sci USA. 1994;91:11914–8. doi: 10.1073/pnas.91.25.11914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Bridgewater M, MacNeil HF, Brading AF. Regulatin of tone in pig urethrl smootth muscle. J Urol. 1993;150:22–8. doi: 10.1016/s0022-5347(17)35451-4. [DOI] [PubMed] [Google Scholar]
  • 10.Teramoto N, Brading AF. Activation by levcromjakalim and metabolic inhibiion of glibenclamide-sensitive K Channels in smooth muscle cells of pig proxiamal urthra. Br J Pharmacol. 1996;118:635–42. doi: 10.1111/j.1476-5381.1996.tb15448.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Hashitani H, Van Helden DF, Suzuki H. Properties of spontanceous depolarizatons in circular smooth muscle cells of rabbit urethra. Br. J Pharamacol. 1996;118:1627–32. doi: 10.1111/j.1476-5381.1996.tb15584.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Smet PJ, Jonavicus J, Marshal VR, De Vente J. Distribution of nitric oxide synthase-immunoreactiv nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience. 1996;71:337–48. doi: 10.1016/0306-4522(95)00453-x. [DOI] [PubMed] [Google Scholar]
  • 13.Thunebeg L. One hunderd years of interstitial cells of Caja. Microse Res Tech. 1999;47:223–38. doi: 10.1002/(SICI)1097-0029(19991115)47:4<223::AID-JEMT2>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  • 14.Burns AJ, Lomax AEJ, Torihashi S, Snaders KM, Ward SM. Interstitial cells of Cajal mediate inhibitory neurotransmisson in the stomach. Proc Natl Acad Sci USA. 1996;93:12008–13. doi: 10.1073/pnas.93.21.12008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ward SM, Morris G, Reese L, Wang XY, Sandres KM. Interstitial cells of Cajal ediate enteric inhibitory neurotrnsmission in the lower esophagela nad pyloric sphicter. Gastroenterology. 1998;115:314–29. doi: 10.1016/s0016-5085(98)70198-2. [DOI] [PubMed] [Google Scholar]
  • 16.Ward SM, Beckeet EAH, Wang XY, Baker F, Khoyi M, Sanders KM. Inersitial cells of Cajal Mediate cholinergic neurotransmission from enteric motor neurons. J Neurosic. 2000;20:1393–403. doi: 10.1523/JNEUROSCI.20-04-01393.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Sergent GP, Hollywood MA, McCloskey KD, Thornbury KD, Mchale NG. Specialised pacemaking cells in the rabbit urethr. J Physiol. 2000;526:359–66. doi: 10.1111/j.1469-7793.2000.t01-2-00359.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.McCloskey KD, Hollywood MA, Thornbury KD, Ward SM, McHale NG. Kit-like immunopositive cells in sheep mesenteric lymphytic vessels. Cell Tissue Res. 2002;310:77–84. doi: 10.1007/s00441-002-0623-y. [DOI] [PubMed] [Google Scholar]
  • 19.Exinatris B, Klemm MF, Lang RJ. Spontaneous slow wave and contractile activity of the guinea pig prosta te. J Urol. 2002;168:315–22. [PubMed] [Google Scholar]
  • 20.Harhun MI, Gordienko DV, Povstyan OV, Moss RF, Bolton TB. Function of interstitial cells of Cajal in the rabbit portal vein. Circ Res. 2004;95:619–26. doi: 10.1161/01.RES.0000143014.04535.a3. [DOI] [PubMed] [Google Scholar]
  • 21.Mccloskey KD, Gurney AM. Kit Positive cells n the guinea pig bladder. J Urol. 2002;168:832–6. [PubMed] [Google Scholar]
  • 22.Propesu LM, Ciontea SM, Crtoiu D, Hinescu ME, Radu E, Ionescu N, Ceausu M, Gherghiceanu M, Bgrga RI, Vasilescu F, Zagrean L, Ardeleanu C. Novel type of intersitial cell (Cajal-like) n human fallopian tube. J Cell MOl Med. 2005;9:523. doi: 10.1111/j.1582-4934.2005.tb00376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Langton P, Ward SM, Carl A, Norell MA, Sanders KM. Spontaneous electrical activity of intersitial cells of Cajal islolated from canine proximal colon. Proc Natl Acad Sci USA. 1989;86:7280–4. doi: 10.1073/pnas.86.18.7280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Rumessen JJ, Thunebeg L. Pacemadker cells in the gastrointerstinal tract: inersitial cells of Cajal. Scand J Gatroenterol Suppl. 1996;216:82–94. doi: 10.3109/00365529609094564. [DOI] [PubMed] [Google Scholar]
  • 25.Thomsen L, Robinson TL, Lee J, Farraway L, Hughes M, Andrew DW, Huizinga JD. Inerstitial cells of Cajal generate a rhythmic pacemaker current. Nat med. 1998;4:848–51. doi: 10.1038/nm0798-848. [DOI] [PubMed] [Google Scholar]
  • 26.Koh SD, Sanders KM, Ward SM. Spntaneous electrical rhythmicity in cultured intersittial cells of cajal from the murine small intestine. J Physiol. 1998;513:203–13. doi: 10.1111/j.1469-7793.1998.203by.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Koh SD, Jun JY, Kim TW. Sanders KM. A Ca2+- inhibited noselective cantion conductance contributes to pacemaker currents in mouseintersitial cell of Cajal. J Physil. 2002;540:803–14. doi: 10.1113/jphysiol.2001.014639. &. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Huizinga JD, Zhu Y, Ye J, Molleman A. High-conductance cholride channlels generate pacemaker curents in interstitial cells of Cajal. Gastroenterology. 2002;123:1627–36. doi: 10.1053/gast.2002.36549. [DOI] [PubMed] [Google Scholar]
  • 29.Walker RL, Koh SD, Sergeant GP, Snadres KM, Horowitz B. TRPC4 currents have properties similoar to the pacemake current in interstitial cells fof Cajal. Am J Physiol Cell Physiol. 2002;283:C1637–45. doi: 10.1152/ajpcell.00266.2002. [DOI] [PubMed] [Google Scholar]
  • 30.Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD. Role of IP(3) in modulation of spontaneous activity n pacemaker cells of rabbit urethra. Am J Physiol Cell Physil. 2001;280:C1349–56. doi: 10.1152/ajpcell.2001.280.5.C1349. [DOI] [PubMed] [Google Scholar]
  • 31.Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K. 2APB, 2-Aminoethoxydiphenyl borate, a membrane-penetrable modulator of ins(1,4,5)P3 induced Ca2+ release. J Biochem. 1997;122:498–505. doi: 10.1093/oxfordjournals.jbchem.a021780. [DOI] [PubMed] [Google Scholar]
  • 32.Johnston L, Sergeant GP, Hollywood MA, Thornbury KD, McHale NG. Calcium oscillatinsin interstitial cells of the rabbit urethra. J Physiol. 2005;565:449–61. doi: 10.1113/jphysiol.2004.078097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Bradley E, Hollywood MA, McHale NG, Thornbury KD, Sergeant GP. Pacemaker acitivity n urethrl interstitial cells is not dependent on capacitaive calcium entry. Am J Physiol Cell Physiol. 2005;289:C625–32. doi: 10.1152/ajpcell.00090.2005. [DOI] [PubMed] [Google Scholar]
  • 34.Bradely E, Hollywood MA, Johnston L, Large RJ, Mastsuda T, Baba A, McHale NG, Thornbury KD, Sergeant GP. 2006. 2+Contribution of Reverse Na+/Ca exchange to spontaneous activity interstitial cells of Cajal in the rabbit urethra J Physiol in press)
  • 35.Putney JW., Jr Pharmacology of capacitivaive calcium entry. Mol interv. 2001;1:84–94. [PubMed] [Google Scholar]
  • 36.Leblanc N, Hume JR. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulam. Science. 1990;248:372–6. doi: 10.1126/science.2158146. [DOI] [PubMed] [Google Scholar]
  • 37.Andersson KE. Pharmacologyof lower urinary tract somoth mucslces and penle erectile tissues. Pharmacol Rev. 1993;45:253–307. [PubMed] [Google Scholar]
  • 38.Sergeant GP, Thornbury KD, McHale NG, Hollywood MA. Characterization of norepinephirine-evoked invward currents in terstital cells isolated from the rabbit urethra. Am J Physiol Celll Physil. 2002;283:C885–94. doi: 10.1152/ajpcell.00085.2002. [DOI] [PubMed] [Google Scholar]
  • 39.Berridge MJ. Insitol trisphosphate and calcium Signalling. Nature. 1993;361:315–23. doi: 10.1038/361315a0. [DOI] [PubMed] [Google Scholar]
  • 40.Somly AV, Bond M, Somlyo AP, Scarpa A. Inositol trisphosphateinduced calcium relese and conraction in vascualr smooth muscle. Proc Natl Acad Sci USA. 1985;82:5231–5. doi: 10.1073/pnas.82.15.5231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Boittin F, Macrez N, Halet G, Mironneau J. Norepinephirin-induced Ca2+ waves depend on insP3 and ryandoine receptor activation in vascualr myocytes. Am J Physiol. 1999;277:C139–51. doi: 10.1152/ajpcell.1999.277.1.C139. [DOI] [PubMed] [Google Scholar]
  • 42.Amedee T, Large WA, Wang Q. Characteristics of Choloride currents activated by noradrenaline in rabbit ear artery cells. J Physiol. 1990;428:501–16. doi: 10.1113/jphysiol.1990.sp018224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Waldeck K, Ny L, Persoson K, Andesson KE. Mediators and mechanisms of relaxationon arabbit urethral smooth muscle. Br J Pharmacol. 1998;123:617–24. doi: 10.1038/sj.bjp.0701645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Brding AF. Spontaneous activity of lower urinary tract smooth mucles: Correlation between ion channels and tissue function. J Physiol. 2006;570:13–22. doi: 10.1113/jphysiol.2005.097311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Brading AF. The physiology of the mammalian urinary ourflow tract. Exp Physiol. 1999;84:215–21. doi: 10.1111/j.1469-445x.1999.tb00084.x. [DOI] [PubMed] [Google Scholar]
  • 46.Thornbury KD, Hollywood MA, McHale NG. Mediationby nitric oxide of neurogenic relaxationof the nurinary bladder neck muscle in sheep. J Physiol. 1992;451:133–44. doi: 10.1113/jphysiol.1992.sp019157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Andersson KE, Wein AJ. Pharmacology of teh lower urinary tract: basis for current and future tretments of urianryincontinence. Pharmacol Rev. 2004;56:581. doi: 10.1124/pr.56.4.4. [DOI] [PubMed] [Google Scholar]
  • 48.Werkstrom V, Alm P, Persson K, Andersson KE. Inhibitory innervation of the guinea-pig urthr; roles of CO, NO and VIP. J Auton Nerv Syst. 1998;74:33–42. doi: 10.1016/s0165-1838(98)00135-0. [DOI] [PubMed] [Google Scholar]
  • 49.Sergeant GP, Johnston L, McHale NG, Thornbury KD, Hollyowood MA. 2006. Activation of the cGMP/PKG pathway inhibits electrical activity in rabiit urethral ICC by reducig the spatial spred of Ca2+ waves J Physiol ; in press.
  • 50.Persson K, Pandita RK, Aszodi A, Ahmad M, Pfeifer A, Fassler R, Andersson KE. Functional charactersiics of urinary tract smooth musclesin mice laking cGMP Protein kinas type I. Am J Physil Regul Ineger Comp Physil. 2000;279:R1112–20. doi: 10.1152/ajpregu.2000.279.3.R1112. [DOI] [PubMed] [Google Scholar]
  • 51.Thind P, Lose G, COlstrup H, Andersson KE. The influence of betaadrenoceptor and muscarinic receptor agonitis and antagonists on the static urethral closure function in healthy female. Scand J Urol Nephrol. 1993;27:31–8. doi: 10.3109/00365599309180411. [DOI] [PubMed] [Google Scholar]
  • 52.Noda K, Takede M, Oka M, Hirouchi M, Ukai Y, Toda N. Functional rolw of inhibitory and excitaroy nerves in the percine lower urinary tract. Eur J Pharmacol. 2002;456:81–90. doi: 10.1016/s0014-2999(02)02585-2. [DOI] [PubMed] [Google Scholar]
  • 53.Van der Werf BA, Creed KE. Mechanical properties and innervation of the smooth muscle layers of the urethra of greythound. BJU int. 2002;90:588–95. doi: 10.1046/j.1464-410x.2002.02971.x. [DOI] [PubMed] [Google Scholar]
  • 54.Creed KE, Oike M, Ito Y. The electrical properites and responces ot nerve stimultin of teh proximal urethr of the male rabbit. Br J Urol. 1997;79:543–53. doi: 10.1046/j.1464-410x.1997.00105.x. [DOI] [PubMed] [Google Scholar]
  • 55.Yamnishi T, Chaple CR, Yasuda K, Yoshida K, Chess-Williams R. The role of M2 muscarinic recptor subtypes mediating contraction of the circualr and longitudinal smooth muscle of the pig proximal urethr. J Urol. 2002;168:308–14. [PubMed] [Google Scholar]
  • 56.Mutoh S, Latifpour J, Saito M, Weiss RM. Evidence for the presence of regional difference in the subtype specificity of muscarinic receptors in rabbit lower urinary tract. J Urol. 1997;157:717–21. [PubMed] [Google Scholar]
  • 57.Biers SM, Reynard JM, Doore T, Bradin AF. The functional effects of a c-kit tyrosine inhibitor on guineapig and human detruso. BJU int. 2006;97:612–6. doi: 10.1111/j.1464-410X.2005.05988.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES