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 Ca²⁺ activates Ca²⁺/calmodulin-dependent myosin light chain kinase-dependent phosphorylation of 20-kDa regulatory light chains of myosin which leads to ureteric contraction. Ca²⁺ entry from the extracellular space via voltage-gated L-type Ca²⁺ channels (VGCCs) provides the major source of activator Ca²⁺, responsible for generation of both the AP and a Ca²⁺ transient that appears as an intercellular Ca²⁺ wave. The AP, inward Ca²⁺ current, Ca²⁺ transient and twitch contraction are all fully blocked by the selective L-type Ca²⁺ channel blocker nifedipine. Ca²⁺ entry via VGCCs, coupled to activation of Ca²⁺-sensitive K⁺ (K_Ca) or Cl^- (Cl_Ca) 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, Ca²⁺ 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 Ca²⁺ 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_Ca current and activation of non-selective cation receptor/store operated channels.