Identification of a region of the N-terminal of the human CCKA receptor essential for the high affinity interaction with agonist CCK.

Abstract

The discovery of an N-terminally truncated isoform of the cholecystokinin A subtype (CCKA) receptor exhibiting an atypical pharmacology led us to study the effects of N-terminal truncation on the pharmacology of the human CCKA receptor. We cloned the cDNA encoding the full CCKA receptor and constructed two truncated forms, one which lacked the first 37 amino acids (CCKAT38) and another which lacked the first 42 amino acids (CCKAT43). Expression of the receptors in COS-7 cells showed that the CCKAT38 receptor displayed a pharmacological profile identical to that of the full receptor. In contrast, the CCKAT43 receptor did not directly bind agonist CCK9; however, the agonist could compete for binding at low affinity sites. Binding of the partial agonist JMV180 and the antagonist JMV179 were unaffected. These results identify for the first time a part of the N-terminal, close to the membrane, of the human CCKA receptor that is essential for the high affinity interaction with CCK.