Abstract
The mechanisms by which cationic amino acids influence pancreatic B-cell function have been studied by monitoring simultaneously (86)Rb(+) efflux and insulin release from perifused rat islets. The effects of two reference amino acids arginine and lysine were compared with those of closely related substances to define the structural requirements for recognition of these molecules as secretagogues. Arginine accelerated (86)Rb(+) efflux and increased insulin release in the absence or in the presence of 7mm-glucose. Its effects on efflux did not require the presence of extracellular Ca(2+) or Na(+), but its insulinotropic effects were suppressed in a Ca(2+)-free medium and inhibited in an Na(+)-free medium. Among arginine derivatives, only 2-amino-3-guanidinopropionic acid mimicked its effects on (86)Rb(+) efflux and insulin release; citrulline, guanidinoacetic acid, 3-guanidinopropionic acid and guanidine were inactive. Norvaline and valine also increased (86)Rb(+) efflux, but their effect required the presence of extracellular Na(+); they did not stimulate insulin release. Lysine as well as the shorter-chain cationic amino acids ornithine and 2,4-diaminobutyric acid accelerated (86)Rb(+) efflux in a Ca(2+)- and Na(+)-independent manner. Their stimulation of insulin release was suppressed by Ca(2+) omission, but only partially inhibited in an Na(+)-free medium. The uncharged glutamine and norleucine increased the rate of (86)Rb(+) efflux in the presence of glucose, only if extracellular Na(+) was present. Norleucine slightly increased release in a Ca(2+)- and Na(+)-dependent manner. The effects of lysine on efflux and release were not mimicked by other related substances such as 1,5-diaminopentane and 6-aminohexanoic acid. The results suggest that the depolarizing effect of cationic amino acids is due to accumulation of these positively charged molecules in B-cells. This causes acceleration of the efflux of K(+) ((86)Rb(+)) and activation of the influx of Ca(2+) (which triggers insulin release). The prerequisite for the stimulation of B-cells by this mechanism appears to be the presence of a positive charge on the side chain of the amino acid, rather than a specific group.