We have examined the region-specific expression of mRNAs for four members of rat FGF receptor family, FGFR-1, FGFR-2 FGFR-3, and FGFR-4, in rat brain by in situ hybridization. The FGFR-1, FGFR-2, and FGFR-3 mRNAs were expressed widely but differentially in the brain. However, the FGFR-4 mRNA was not expressed in the brain. The FGFR-1 mRNA was strongly expressed in several regions including the hippocampus, cerebellum, and pedunculopotine tegmental nucleus. The FGFR-2 mRNA expression was high in the choroid plexus, and moderate in the fiber-rich regions (the corpus callosum, external capsule, and internal capsule) and the olfactory bulb. The FGFR-3 mRNA was expressed diffusely in the brain. We have also examined the cellular localization of these mRNAs in the brain. Although the FGFR-1 mRNA was expressed preferentially in neurons, the FGFR-2 and FGFR-3 mRNAs were expressed preferentially in glial cells. The present findings that the FGFR-1, FGFR-2, and FGFR-3 mRNAs were expressed widely but with region- and cell-specificity in the brain indicate that these receptors have different roles in the brain.

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The pharmacological profile of a new CCKA receptor antagonist, T-0632 [sodium (S)-3-[1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinyl)-carbonyl] amino-6-methoxy-2-oxo-1-H-indole]propanoate], was examined in in vitro studies and compared with those of L-364,718 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-1H-indole-2-carboxamide] and loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid]. T-0632 inhibited the specific binding of [125I]CCK-8 to rat pancreatic CCKA receptor in a concentration-dependent and competitive manner. The Ki value of T-0632 for the CCKA receptor was estimated to be 0.24 nM, which was 23 000-fold less than the Ki value (5600 nM) for guinea pig CCKB receptor. L-364,718 and loxiglumide were 1500- and 64-fold selective for CCKA over CCKB receptor, respectively. T-0632, L-364,718 and loxiglumide inhibited CCK-8 (100 pM)-stimulated amylase release from rat pancreatic acini in a concentration-dependent manner with IC50 values of 5.0 nM, 5.0 nM and 3.0 microM, respectively. In the isolated rabbit gallbladder smooth muscle, T-0632 and loxiglumide competitively inhibited CCK-8-induced contraction with pA2 values of 8.5 and 7.0, respectively. However, L-364,718 showed an apparent non-competitive antagonism. The IC50 values of T-0632, L-364,718 and loxiglumide for CCK-8 (30 nM)-induced contraction were 31 nM, 4.9 nM and 1300 nM, respectively. The inhibitory effects of T-0632 and loxiglumide in gallbladder smooth muscle were readily reversible, but L-364,718 showed a long-lasting inhibition. These results suggest that T-0632 is a potent, reversible and more selective CCKA receptor antagonist compared with L-364,718 and loxiglumide.