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Volume 17, Number 5, Issue of March 1, 1997 pp. 1795-1803
Copyright ©1997 Society for Neuroscience

Differential Binding Profile and Internalization Process of Neurotensin via Neuronal and Glial Receptors

Received Sept. 20, 1996; revised Dec. 5, 1996; accepted Dec. 12, 1996.

Dominique Nouel¹, Marie-Pierre Faure¹, Jacques-André St. Pierre², Richard Alonso², Rémi Quirion², and Alain Beaudet¹

¹ Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada, H3A 2B4, and ² Douglas Hospital Research Center and Department of Psychiatry, McGill University, Verdun, Quebec, Canada, H4H 1R3

Two G-protein-coupled receptors for the tridecapeptide neurotensin (NT) have been identified and cloned in mammalian brain: a high-affinity (K_d = 0.3 nM) receptor, sensitive to the antagonist SR 48692 but insensitive to levocabastine, and a lower-affinity (K_d = 2-4 nM) receptor, sensitive to levocabastine but with poor affinity for SR 48692. Although there is good evidence that the high-affinity site is predominantly expressed in neurons, little is known of the cellular localization of the low-affinity receptor. In the present study, we identify by confocal microscopy selective levocabastine-sensitive, SR 48692-resistant binding of a fluorescent derivative of NT (fluo-NT) to a subpopulation of glial fibrillary acidic protein-immunoreactive glial cells grown in culture from the midbrain and cerebral cortex of embryonic and neonatal rats, respectively. We also demonstrate, by combining fluo-NT detection with tyrosine hydroxylase immunofluorescence, that these glial binding sites are differentially regulated from the SR 48692-sensitive NT receptor expressed in the same cultures by mesencephalic dopamine neurons. Whereas the latter undergoes rapid ligand-induced internalization followed by centripetal mobilization of ligand-receptor complexes from processes to perikarya and from perikaryal periphery to cell center, the former induces the formation of cell-surface clusters that fail to internalize. It is concluded that NT may exert its effects on both neurons and astrocytes in the CNS. Whereas NT neural signaling is exerted through high-affinity receptors and may be partly effected through internalization of receptor-ligand complexes, glial signaling is exerted through low-affinity NT receptors and appears to be transduced exclusively at the level of the plasma membrane.

Key words: confocal microscopy; immunohistochemistry; tyrosine hydroxylase; dopamine; glial fibrillary acid protein; endocytosis; midbrain

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