CALCIUM-SENSITIZING FUNCTION FOR THE DIPEPTIDE CARNOSINE IN SKELETAL-MUSCLE CONTRACTILITY

Carnosine (alpha-alanyl-l-histidine), a dipeptide, the exact functions of which are unknown, is found at millimolar concentrations in muscle cells. In skinned skeletal muscle fibers, carnosine released calcium from the sarcoplasmic reticulum and generated tension, and carnosine ( ED50 = 6.6 mM) was less potent than caffeine (ED50 = 1.5 mM). The effe ct of carnosine on the ryanodine receptor calcium release channel(Ry1) was investigated in single Ry1 molecules incorporated into an artific ial lipid bilayer for recording channel activity. Carnosine (0.1-10 mM ) increased open-state probability (Po) of Ry1 with a fourfold maximal increase occurring at 2.5 mM. Carnosine (5 mM) caused a twofold incre ase in the open-state dwell time. Carnosine also altered the Ry1 chann el's response to changes in calcium concentration, shifting the Po-ver sus-pCa relationship to the left. The presence of carnosine at a milli molar concentration in muscle cells and its effects on the major calci um release channel in skeletal muscle suggest an important function fo r this unique dipeptide in regulation of contractility. One possible f unction of carnosine is the sensitization of key proteins to activatio n and/or inactivation by Ca2+.