Regulation of gastrointestinal motility by Ca²⁺/calmodulin-stimulated protein kinase II

Gastrointestinal (GI) motility ultimately depends upon the contractile activity of the smooth muscle cells of the tunica muscularis. Integrated functioning of multiple tissues and cell types, including enteric neurons and interstitial cells of Cajal (ICC) is necessary to generate coordinated patterns of motor activity that control the movement of material through the digestive tract. The neurogenic mechanisms that govern GI motility patterns are superimposed upon intrinsic myogenic mechanisms regulating smooth muscle cell excitability. Several mechanisms regulate smooth muscle cell responses to neurogenic inputs, including the multifunctional Ca²⁺/calmodulin-stimulated protein kinase II (CaMKII). CaMKII can be activated by Ca²⁺ transients from both extracellular and intracellular sources. Prolonging the activities of Ca²⁺-sensitive K⁺ channels in the plasma membrane of GI smooth muscle cells is an important regulatory mechanism carried out by CaMKII. Phospholamban (PLN) phosphorylation by CaMKII activates the sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA), increasing both the rate of Ca²⁺ clearance from the myoplasm and the frequency of localized Ca²⁺ release events from intracellular stores. Overall, CaMKII appears to moderate GI smooth muscle cell excitability. Finally, transcription factor activities may be facilitated by the neutralization of HDAC4 by CaMKII phosphorylation, which may contribute to the phenotypic plasticity of GI smooth muscle cells.