Programme Contents

Spontaneous electrical and Ca²⁺ signals in the mouse renal pelvis that drive pyeloureteric peristalsis

Pacemakers are ubiquitous throughout the body, setting all sorts of global rhythms, such as diurnal and circadian rhythms, as well as local rhythms that drive the heart and a number of smooth muscle organs. The upper urinary (pyeloureteric) system, consisting of the renal pelvis and ureter, is unique in physiology in that morphological, electrophysiological and Ca²⁺ imaging evidence suggests the presence of two putative pacemaker cell populations: atypical smooth muscle cells (SMCs) situated mostly in the proximal renal pelvis (Lang et al., 2007a,b) and interstitial cells which are distributed throughout the pyeloureteric system and identified by their distinctive spindle- or stellate-shaped morphology and their immuno-reactivity to antibodies raised against the receptor tyrosine kinase, Kit (Pezzone, 2003).
We have recently established in excised strips (Lang et al., 2007a) or single cells (Lang et al., 2007b) of the mouse renal pelvis that:

1. nifedipine-sensitive action potentials and Ca²⁺ waves within the SMC wall are responsible for the peristaltic contractions that propagate the length of the pyeloureteric system.
2. spindle-shaped atypical SMCs display high frequency spontaneous transient depolarizations (STDs) and Ca²⁺ transients that are reduced but not blocked by nifedipine or ryanodine. Under perforated-patch voltage clamp, a subpopulation of single SMCs displayed spontaneous transient inward currents (STICs) and long-lasting large inward currents (LICs) that could well be responsible for STD generation.
3. interstitial cells with a morphology and distribution similar to Kit-positive cells display low frequency Ca²⁺ signals that are insensitive to nifedipine but readily blocked by ryanodine. These Ca²⁺ signals have time courses and frequencies similar to the long-lasting nifedipine-insensitive depolarizations recorded with intracellular microelectrodes. After enzymatic dispersal, two distinct populations of interstitial cells display STICS and LICs that are also little affected by 1 mM nifedipine and likely to be cation selective.

We have concluded that reduction but not blockade of STDs in atypical SMCs by nifedipine or ryanodine suggests that Ca²⁺ entry through L type Ca²⁺ channels and Ca²⁺-induced release of Ca²⁺ (CIRCa) from internal stores is involved in the synchronization and propagation (entrainment) of STDs before they can provide a pacemaker drive to the SMC wall. However, the site of this entrainment that triggers a propagating contraction has yet to be established. Pelviureteric interstitial cells also generate their own non-propagating spontaneous electrical and Ca²⁺ signals albeit at a lower frequency than atypical SMCs. It is not yet clear, however, whether these spontaneously-active cells are indeed Kit-positive interstitial cell of Cajal-like cells and not other interstitial cells such as macrophages or fibroblasts, etc.

Lang RJ, Hashitani H, Tonta MA, Parkington HC, Suzuki H. (2007a) Journal of Physiology, 583: 1049-68.

Lang RJ, Zoltkowski BZ, Hammer JM, Meeker WF, Wendt I. (2007b) Journal of Urology, 177: 1573-80.

Pezzone MA. (2003) American Journal of Physiology, 284: 925-9.