In the retina, somatostatin (SST), an inhibitory peptide that influences neuronal activity, is predominantly expressed by sparsely occurring amacrine cells. The SST subtype 2A receptor is expressed by rod bipolar cells, including their axonal terminals. We used Ca2+-imaging techniques and the ratiometric Ca2+ indicator dye fura-2 AM to investigate Ca2+ dynamics in rod bipolar cell terminals. Depolarization of rod bipolar cells by the addition of high K+ (50 or 100 mM) elicited a sustained increase in [Ca2+]i in rod bipolar terminals that returned to basal levels following K+ removal. The Ca2+ response was dependent on extracellular Ca2+, and was inhibited by the Ca2+ channel blocker Cd2+ and by the selective L-type Ca2+ channel blocker, nimodipine. SST inhibited a K+ depolarization-induced [Ca2+]i response in rod bipolar terminals. This inhibition was observed with 1 nM SST and was maximal with 1 μM SST. These findings indicate that SST may regulate transmitter release from rod bipolar terminals by activating the SST subtype 2A receptor through modulation of intracellular Ca2+.