Calcitonin gene-related peptide (CGRP) was examined for its effects on intracellular free Ca 2 + concentration ([Ca 2 + ] i ) in UMR 106 osteoblast-like cells. Cells loaded with the Ca 2 + dye FURA-2 dose-dependently responded to CGRP (1-100 nM) with transient two-fold increases in [Ca 2 + ] i . An intracellular source for this Ca 2 + transient was suggested by the failure of membrane depolarization with high extracellular K + or acute depletion of extracellular Ca 2 + ([Ca 2 + ] e ) with EGTA to attenuate this response. After cells were incubated for 45 min with 0.1 mM extracellular Ca 2 + to deplete intracellular Ca 2 + stores, CGRP produced a 25-30% decrease in [Ca 2 + ] i rather than a transient increase. This calcium decrease was mimicked by membrane depolarization or by pinacidil, a specific activator of adenosine triphosphate (ATP)-sensitive potassium (K A T P ) channels, and blocked by glybenclamide, a specific blocker of K A T P channels. Our data suggest that CGRP has diverse Ca 2 + regulatory effects in UMR 106 cells, mobilizing Ca 2 + from intracellular stores via classical signaling while possibly promoting cellular Ca 2 + efflux or inhibiting uptake through voltage-dependent Ca 2 + channels via K A T P -mediated hyperpolarization.