Advances in Understanding Calcium Sensitization in Gastrointestinal Smooth Muscles: Pathways, Interstitial Cells, and Disease

Contractile activity of gastrointestinal smooth muscles is triggered by increased intracellular Ca 2+ , which activates myosin light chain kinase (MLCK) and leads to phosphorylation of myosin regulatory light chain (RLC), enabling contraction.Myosin light chain phosphatase (MLCP) dephosphorylates RLC for relaxation.The balance between MLCK and MLCP determines the relationship between calcium levels and contractile force.Shifting the balance between MLCK and MLCP in favor of MLCK by inhibiting MLCP allows MLCK to phosphorylate more RLC and generate increased force at any given Ca 2+ concentration.Thus, when MLCP is inhibited, the myofilaments are more sensitive to calcium, allowing greater force at any given Ca 2+ concentration.Major mechanisms for calcium sensitization in GI smooth muscle include protein kinase C-mediated phosphorylation of protein phosphatase 1 regulatory subunit 14A (CPI-17) and Rho-associated coiledcoil kinase 2 (ROCK2)-mediated phosphorylation of myosin phosphatase targeting subunit 1. Calcium sensitization is crucial for sphincter tone, sustained contraction, peristalsis, energy conservation, and coordinated motility.Smooth muscle cells, interstitial cells of Cajal, and platelet-derived growth factor alpha positive (PDGFRα + ) cells form the SIP syncytium, which regulates excitability and calcium sensitization.This review updates our current understanding of the regulatory mechanisms of calcium sensitization with the recent findings from genetically engineered mice with deficiencies in protein kinase C and ROCK2 calcium sensitization pathways, and the involvement of interstitial cells in regulating GI smooth muscle cell excitability.Dysregulated calcium sensitization pathways in motility disorders are summarized, to potentially aid in the development of new pharmacological strategies to prevent and treat GI motility disorders.