IDENTIFICATION OF A REGION OF THE N-TERMINAL OF THE HUMAN CCKA RECEPTOR ESSENTIAL FOR THE HIGH-AFFINITY INTERACTION WITH AGONIST CCK

The discovery of an N-terminally truncated isoform of the cholecystoki nin A subtype (CCKA) receptor exhibiting an atypical pharmacology led us to study the effects of N-terminal truncation on the pharmacology o f the human CCKA receptor. We cloned the cDNA encoding the full CCKA r eceptor and constructed two truncated forms, one which lacked the firs t 37 amino acids (CCKAT38) and another which lacked the first 42 amino acids (CCKAT43). Expression of the receptors in COS-7 cells showed th at the CCKAT38 receptor displayed a pharmacological profile identical to that of the full receptor. In contrast, the CCKAT43 receptor did no t directly bind agonist CCK9; however,the agonist could compete for bi nding 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 hu man CCKA receptor that is essential for the high affinity interaction with CCK. (C) 1995 Academic Press, Inc.