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Vol. 54, Issue 2, 364-371, August 1998
Institut National de la Santé et de la Recherche
Médicale U 151, CHU Rangueil, Bat L3, 31403 Toulouse Cedex,
France (S.S.-P., C.E.), and
Digestive Diseases Branch, National
Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, Maryland 20892-1804
The cholecystokinin (CCK) receptor types A and B (CCKAR and CCKBR) are
G protein-coupled receptors with approximately 50% amino acid
identity; both have high affinity for the sulfated CCK octapeptide
(CCK-8), whereas only the CCKBR has high affinity for gastrin.
Previously, we identified five amino acids in the second extracellular
loop (ECL) of the CCKBR that were essential for gastrin selectivity.
Subsequent mutagenesis of one of these five amino acids (H207F)
resulted in the loss of radiolabeled CCK-8 binding. CCK-8 stimulated
total inositol phosphate accumulation in COS-1 cells transiently
expressing the CCKBR-H207F with full efficacy and a 3044-fold reduced
potency, which suggests that the loss of radioligand binding was caused
by a loss in affinity. Alanine scanning mutagenesis was performed on
the amino terminus near the top of transmembrane domain I (TMI) and on
ECL1, two extracellular domains implicated in ligand binding by
previous mutagenesis studies.
125I-Bolton-Hunter-CCK-8 binding to mutant receptors
transiently expressed in COS-1 identified one nonconserved amino acid,
R57A, at the top of TMI that caused a 21-fold reduction in CCK-8
affinity and four conserved amino acids, N115A, L116A, F120A and F122A, in the ECL1 that caused a 15.6-, 6-, 440-, and 8-fold reduction in
affinity or efficacy. Alanine substitution of the equivalent amino
acids in the CCKAR corresponding to each of the five amino acids in
ECL1 and ECL2 affecting CCK-8 affinity for the CCKBR revealed only two
mutations, L103A and F107A, that decreased CCK-8 affinity (68- and
2885-fold, respectively). These data suggest that CCK-8 interacts at
multiple contact points in the extracellular domains of CCK receptors
and that the CCKAR and CCKBR have distinct binding sites despite their
shared high affinity for CCK-8.
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