We have previously shown that secondmessenger-dependent kinases (cAMP-dependent kinase, protein kinase C) in the olfactory system are essential in terminating second-messenger signaling in response to odorants. We now document that subtype 2 of the ,B-adrenergic receptor kinase (fARK) is also involved in this process. By using subtype-specific antibodies to .ARK-1 and I3ARK-2, we show that flARK-2 is preferentially expressed in the olfactory epithelium in contrast to 'mdings in most other tissues. Heparin, an inhibitor of DARK, as well as anti-flARK-2 antibodies, (i) completely prevents the rapid decline of second-messenger signals (desensitization) that follows odorant stimulation and (ii) strongly inhibits odorant-induced phosphorylation of olfactory ciliary proteins. In contrast, (6ARK-1 antibodies are without effect. Inhibitors ofprotein kinase A and protein kinase C also block odorant-induced desensitization and phosphorylation. These data suggest that a sequential interplay of secondmessenger-dependent and receptor-specific kinases is functionally involved in olfactory desensitization.The olfactory system responds precisely to iterative stimulation (1) and thus can continuously monitor changes in the odorous environment occurring between consecutive sniffs. This sensory behavior is due to characteristic phasic responses of receptor cells to short odor pulses (2), thereby preventing a brief stimulus from being perceived as continuous smell. The basis for this characteristic feature of olfactory neurons is a rapid termination of the odor-induced primary reaction-i.e., the second-messenger cascade initiated by an odorant-occupied receptor is rapidly turned off (3,4). Recent studies have indicated that olfactory signaling is terminated by uncoupling the transduction cascade; this is accomplished via a negative-feedback reaction controlled by the second messenger elicited upon odor stimulation. Second-messenger-activated protein kinases [protein kinase A (PKA) or protein kinase C (PKC)] presumably phosphorylate elements of the transduction apparatus and thereby uncouple the signaling cascade (5). Subsequent experiments have shown that stimulation with odorants indeed caused significant phosphorylation of olfactory ciliary proteins, and there is some circumstantial evidence indicating that receptor proteins for odorants may be modified via second-messengercontrolled protein kinases (6). The emerging picture for signal termination in olfaction is, in many respects, reminiscent of desensitization phenomena in other systems-notably the visual and hormonal signaling pathways, where phosphorylation of receptors in an active state uncouples the reaction cascade by preventing further stimulation ofG proteins (7,8).For the most widely studied model, the p-adrenergic system, two distinct pathways for phosphorylation and desensitization have recently been discovered. Receptor phosphorylation and cascade uncoupling may be mediated either by a cAMP-dependent protein kinase (PKA) or alternatively by a cAMP-independen...