Alternative splicing in the N-terminal extracellular domain of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor modulates receptor selectivity and relative potencies of PACAP-27 and PACAP-38 in phospholipase C activation.
Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides of the vasoactive intestinal peptide/secretin/glucagon family. We previously described alternative splicing of the region encoding the third intracellular loop of the PACAP receptor generating six isoforms with differential signal transduction properties (Spengler, D., Waeber, C., Pantaloni, C., Holsboer, F., Bockaert, J., Seeburg, P. H., and Journot, L. (1993) Nature 365, 170-175). In addition, we demonstrated that the potencies of the two forms of PACAP are similar for adenylate cyclase stimulation, whereas PACAP-38 is more potent than PACAP-27 in phospholipase C activation. In the present work, we document the existence of a new splice variant of the PACAP receptor that was characterized by a 21-amino-acid deletion in the N-terminal extracellular domain. We demonstrate that this domain modulates receptor selectivity with respect to PACAP-27 and -38 binding and controls the relative potencies of the two agonists in phospholipase C stimulation.
Pantaloni
C
C
CNRS-UPR 9023, Centre CNRS-INSERM de Pharmacologie-Endocrinologie, rue de la Cardonille, F-34094 Montpellier Cedex 05, France.
Brabet
P
P
Bilanges
B
B
Dumuis
A
A
Houssami
S
S
Spengler
D
D
Bockaert
J
J
Journot
L
L
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D018076:DNA, Complementary / Q000302:isolation & purification; D004789:Enzyme Activation; D004996:Ethidium; D005091:Exons; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016133:Polymerase Chain Reaction; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism*
C495401:ADCYAP1 protein, human; C495503:ADCYAP1R1 protein, human; C495402:Adcyap1 protein, mouse; D018076:DNA, Complementary; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D004247:DNA; D010738:Type C Phospholipases; D004996:Ethidium