Abstract
Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit regular Ca2+ oscillations that are associated with spontaneous transient inward currents (STICs) recorded under voltage clamp. Their frequency is known to be very sensitive to external Ca2+ concentration but the mechanism of this has yet to be elucidated. In the present study experiments were performed to assess the role of Na+-Ca2+ exchange (NCX) in this process. Membrane currents were recorded using the patch clamp technique and measurements of intracellular Ca2+ were made using fast confocal microscopy. When reverse mode NCX was enhanced by decreasing the external Na+ concentration [Na+]o from 130 to 13 mM, the frequency of global Ca2+ oscillations and STICs increased. Conversely, inhibition of reverse mode NCX by KB-R7943 and SEA0400 decreased the frequency of Ca2+ oscillations and STICs. Application of caffeine (10 mM) and noradrenaline (10 microM) induced transient Ca2+-activated chloride currents (I(ClCa)) at -60 mV due to release of Ca2+ from ryanodine- and inositol trisphosphate (IP3)-sensitive Ca2+ stores, respectively, but these responses were not blocked by KB-R7943 or SEA0400 suggesting that neither drug blocked Ca2+-activated chloride channels or Ca2+ release from stores. Intact strips of rabbit urethra smooth muscle develop spontaneous myogenic tone. This tone was relaxed by application of SEA0400 in a concentration-dependent fashion. Finally, single cell RT-PCR experiments revealed that isolated ICC from the rabbit urethra only express the type 3 isoform of the Na+-Ca2+ exchanger (NCX3). These results suggest that frequency of spontaneous activity in urethral ICC can be modulated by Ca2+ entry via reverse NCX.
Highlights
Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit regular Ca2+ oscillations that are associated with spontaneous transient inward currents (STICs) recorded under voltage clamp
ICC produced regularly occurring Ca2+ oscillations under control conditions which doubled in frequency when [Na+]o was reduced to 13 mm (Fig. 1A)
The intracellular Ca2+ release mechanisms were clarified in a recent study by Johnston et al (2005). They demonstrated that spontaneous global Ca2+ oscillations in ICC arose from the conversion of localized Ca2+ release from ryanodine receptors (RyRs) to propagating Ca2+ waves by activation of IP3 receptors (IP3Rs)
Summary
Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit regular Ca2+ oscillations that are associated with spontaneous transient inward currents (STICs) recorded under voltage clamp. Their frequency is known to be very sensitive to external Ca2+ concentration but the mechanism of this has yet to be elucidated. Spontaneous myogenic tone generated by the smooth muscle wall of the urethra is associated with the occurrence of spontaneous electrical slow waves (Hashitani et al 1996; Hashitani & Edwards, 1999) These events are similar to those which have been recorded in the gastro-intestinal (GI) tract where they originate in specialized pacemaker cells known as interstitial cells of Cajal (ICC; Sanders, 1996). Entry pathways involved remain unknown, though the failure of nifedipine (10 μm) to affect STICs at −60 mV or Ca2+ oscillations (Sergeant et al 2001; Johnston et al 2005) suggests that L-type Ca2+ channels are not involved. Bradley et al (2005) investigated the hypothesis that Ca2+
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