title: Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5.
abstract: In animal models of Parkinson's disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department Experimental Medical Sciences, Lund University, BMC F11, 221 84 Lund, Sweden, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Tim
authors.initials: T
authors.lastname: Fieblinger
authors.forename: Irene
authors.initials: I
authors.lastname: Sebastianutto
authors.forename: Cristina
authors.initials: C
authors.lastname: Alcacer
authors.forename: Zisis
authors.initials: Z
authors.lastname: Bimpisidis
authors.forename: Natallia
authors.initials: N
authors.lastname: Maslava
authors.forename: Sabina
authors.initials: S
authors.lastname: Sandberg
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology*; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018663:Adrenergic Agents; D018491:Dopamine Agonists; C583261:Drd1 protein, mouse; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D013844:Thiazoles; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
keywords: D1 receptor; ERK1/2; Parkinson's disease; dopamine; mGluR5; striatum