Zn²⁺ is abundant in the brain, where it plays a role in the function of a number of enzymes, structural proteins, and transcription factors. Zn²⁺ is also found in synaptic vesicles and is released into synapses achieving concentrations in the range of 100 to 300 μM [Proc Natl Acad Sci USA1997;94:13386–13387; Mol Pharmacol1997;51:1015–1023]. Therefore, Zn²⁺may play a physiological role in regulating the function of postsynaptic channels and receptors. We characterized the effect of Zn²⁺ on the functional properties of the β₂-adrenergic receptor (β₂AR). We found that physiological concentrations of Zn²⁺ increased agonist affinity and enhanced cAMP accumulation stimulated by submaximal concentrations of the βAR agonist isoproterenol. These results provide evidence that Zn²⁺ released at nerve terminals may modulate signals generated by the β₂AR in vivo.