Excitation-Contraction Coupling in Ureteric Smooth Muscle: Mechanisms Driving Ureteric Peristalsis.

The ureter acts as a functional syncytium and is controlled by a propagating plateau-type action potential (AP) which gives rise to a wave of contraction (ureteral peristalsis) via a process called excitation-contraction (E-C)coupling. The second messenger Ca activates Ca/calmodulin-dependent myosin light chain kinase-dependent phosphorylation of 20-kDa regulatory light chains of myosin which leads to ureteric contraction. Ca entry from the extracellular space via voltage-gated L-type Ca channels (VGCCs) provides the major source of activator Ca, responsible for generation of both the AP and a Ca transient that appears as an intercellular Ca wave. The AP, inward Ca current, Ca transient and twitch contraction are all fully blocked by the selective L-type Ca channel blocker nifedipine. Ca entry via VGCCs, coupled to activation of Ca-sensitive K (K) or Cl (Cl) channels, acts as a negative or positive feedback mechanism, respectively, to control excitability and the amplitude and duration of the plateau component of the AP, Ca transient and twitch contraction. The ureter, isolated from the pelvis, is not spontaneously active. However, spontaneous activity can be initiated in the proximal and distal ureter by a variety of biological effectors such as neurotransmitters, paracrine, endocrine and inflammatory factors. Applied agonists depolarise ureteric smooth muscles cells to threshold of AP activation, initiating propagating intercellular AP-mediated Ca waves to produce antegrade and/or retrograde ureteric peristalsis. Several mechanisms have been proposed to describe agonist-induced depolarization of ureteric smooth muscle, which include suppression of K channels, stimulation of Cl current and activation of non-selective cation receptor/store operated channels.