Species differences between rat and mouse CCKA receptors determine the divergent acinar cell response to the cholecystokinin analog JMV-180

The cholecystokinin (CCK) analog JMV-180 acts as a partial agonist in rats and a full agonist in mice. Whether this functional variability is due to species differences in CCK receptor structure or to alterations in the cellular environment is unknown. To address this question, an adenoviral construct encoding the rat CCKA receptor (AdCCK(A)R) was used to express the rat receptor in acini from CCK, receptor-deficient mice (CCKAR -/-). Infection of CCKAR -/- acini in vitro with pAdCCK(A)R led to a time-dependent increase in I-125-CCK8 binding. The affinity for JMV-180 of the adenovirally transferred rat and the endogenous mouse CCKA receptors was not different. In native mouse acini, JMV-180 acted as a full agonist (both stimulation and inhibition of amylase release). In contrast, in mouse acini expressing pAdCCKAR JMV-180 acted as a partial agonist (only stimulation of amylase release). In addition, the pattern of protein synthesis induced by JMV-180 in CCKAR -/- mouse acini infected with AdCCK(A)R resembled the pattern observed in wild-type rats (lack of inhibition) rather than the respective pattern in wild-type mice (inhibition). These data suggest that species differences in the CCKA receptor of rats and mice account for the observed divergence in the acinar cell response to JMV-180.