SEQUENCE-DEPENDENT INTERACTIONS BETWEEN TRANSIENT CALCIUM AND TRANSMITTER STIMULI IN ACTIVATION OF MAMMALIAN BRAIN ADENYLYL-CYCLASE

Recent evidence implicates Ca2+/CaM-sensitive adenylyl cyclase (AC) as a molecular coincidence detector for temporally paired stimuli during associative learning. During conditioning in Aplysia, AC is optimally activated when Ca2+ influx, the cellular signal for the conditioned s timulus (CS), precedes binding of modulatory transmitter, the cellular signal for the unconditioned stimulus (US). This sequence preference of the AC for Ca2+-before-transmitter, parallels the CS-preceding-US p airing requirement of classical conditioning. In this study, we have e xamined the response of AC from rat cerebellum to brief exposures to C a2+ and to transmitter in a perfused membrane assay. We observed modes t synergism between Ca2+ and transmitter in activating AC. Activation was more effective when a Ca2+ stimulus immediately preceded a transmi tter stimulus than when the two stimuli were delivered in the reverse order. Thus, rat cerebellar AC displayed a sequence preference for opt imal activation by paired stimuli similar to that observed in Aplysia; this sequence dependence could contribute to the CS-US sequence requi rement observed in most mammalian classical conditioning paradigms. (C ) 1998 Elsevier Science B.V. All rights reserved.