Electrophysiological and microfluorimetric techniques were used to determine whether intracellular photorelease of caged IP3, and the consequent release of Ca(2+), could trigger a Ca(2+)-activated K(+) current (IIP3). Photorelease of caged IP3 evoked an IIP3 that averaged 2.36 +/- 0.35 pA/pF in 24 of 28 rabbit primary vagal sensory neurons (nodose ganglion neurons, NGNs) voltage-clamped at -50 mV. IIP3 was abolished by intracellular BAPTA (2 mM), a Ca(2+) chelator. Changing the K(+) equilibrium potential by increasing extracellular K(+) ion concentration caused a predicted Nernstian shift in the reversal potential of IIP3. These results indicated that IIP3 was a Ca(2+)-dependent K(+) current. IIP3 was unaffected by three common antagonists of Ca(2+)-activated K(+) currents: bath-applied iberiotoxin (50 nM) or apamin (100 nM), and intracellular 8-Br-cAMP (100 mM) included in the patch pipette. We have previously demonstrated that both IP3-evoked Ca(2+) release and Ca(2+)-induced Ca(2+) release (CICR) are co-expressed in NGNs, and that CICR can trigger a Ca(2+)-activated K(+) current. In the present study, using caffeine, a CICR agonist, to selectively attenuate intracellular Ca(2+) stores, we showed that IP3-evoked Ca(2+) release occurs independently of CICR, but interestingly, that a component of IIP3 requires CICR. These data suggest that IP3-evoked Ca(2+) release activates a K(+) current that is pharmacologically distinct from other Ca(2+)-activated K(+) currents in NGNs. We describe several models that explain our results based on Ca(2+) signaling microdomains in NGNs.