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 stimulus (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 pairing requirement of classical conditioning. In this study, we have examined the response of AC from rat cerebellum to brief exposures to Ca²⁺ and to transmitter in a perfused membrane assay. We observed modest synergism between Ca²⁺ and transmitter in activating AC. Activation was more effective when a Ca²⁺ stimulus immediately preceded a transmitter stimulus than when the two stimuli were delivered in the reverse order. Thus, rat cerebellar AC displayed a sequence preference for optimal activation by paired stimuli similar to that observed in Aplysia; this sequence dependence could contribute to the CS-US sequence requirement observed in most mammalian classical conditioning paradigms.