title: Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration.
abstract: G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Jenkins
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Pekka
authors.initials: P
authors.lastname: Poutiainen
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Ji-Kyung
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Zhaoda
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Surgical Oncology, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Darshini
authors.initials: D
authors.lastname: Kuruppu
authors.affiliation: Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.
authors.forename: Nurgul
authors.initials: N
authors.lastname: Aytan
authors.affiliation: Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Dedeoglu
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 13th Street, Charlestown, MA 02129, USA. Electronic address: abrownell@partners.org.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; C108823:metabotropic glutamate receptor 4
keywords: Metabotropic glutamate receptor; Parkinson's disease; Pharmacological magnetic resonance imaging; Positron emission tomography; mGlu(4); mGlu(5)