DISTRIBUTION OF GLP-1 BINDING-SITES IN THE RAT-BRAIN - EVIDENCE THAT EXENDIN-4 IS A LIGAND OF BRAIN GLP-1 BINDING-SITES

The distribution and biochemical properties of glucagon-like peptide ( GLP)-1(7-36)amide (GLP-1) binding sites in the rat brain were investig ated. By receptor autoradiography of tissue sections, the highest dens ities of [I-125]GLP-1 binding sites were identified in the lateral sep tum, the subfornical organ (SFO), the thalamus, the hypothalamus, the interpenduncular nucleus, the posterodorsal tegmental nucleus, the are a postrema (AP), the inferior olive and the nucleus of the solitary tr act (NTS). Binding studies with [I-125][Tyr39]exendin-4, a GLP-1 recep tor agonist, showed an identical distribution pattern of binding sites . Binding specificity and affinity was investigated using sections of the brainstem containing the NTS. Binding of [I-125]GLP-1 to the NTS w as inhibited concentration-dependently by unlabelled GLP-1 and [Tyr39] exendin-4 with K-l values of 3.5 and 9.4 nM respectively. Cross-linkin g of hypothalamic membranes with [I-125]GLP-1 or [I-125][Tyr39]exendin -4 identified a single ligand-binding protein complex with a molecular mass of 63 000 Da. The fact that no GLP-1 binding sites were detected in the cortex but that they were detected in the phylogenetically old est parts of the brain emphasizes that GLP-1 may be involved in the re gulation of vital functions. In conclusion, the biochemical data suppo rt the idea that the central GLP-1 receptor resembles the peripheral G LP-1 receptor. Furthermore, the presence of GLP-1 binding sites in the circumventricular organs suggests that these may be receptors which a ct as the target for both peripheral blood-borne GLP-1 and GLP-1 in th e nervous system.