The metabotropic glutamate receptor 5 role on motor behavior involves specific neural substrates.

BACKGROUND: The metabotropic glutamate receptor 5 (mGluR5) is involved in various brain functions, including memory, cognition and motor behavior. Regarding locomotor activity, we and others have demonstrated that pharmacological antagonism of mGluR5 promotes hyperkinesia in mice. Moreover, increased locomotor activity can also be observed in mice following the genetic deletion of mGluR5. However, it is still unclear which specific brain substrates contribute to mGluR5-mediated regulation of motor function. RESULTS: Thus, to better understand the role of mGluR5 in motor control and to determine which neural substrates are involved in this regulation we performed stereotactic microinfusions of the mGluR5 antagonist, MPEP, into specific brain regions and submitted mice to the open field and rotarod apparatus. Our findings indicate that mGluR5 blockage elicits distinct outcomes in terms of locomotor activity and motor coordination depending on the brain region injected with mGluR5 antagonist. MPEP injection into either the dorsal striatum or dorsal hippocampus resulted in increased locomotor activity, whereas MPEP injection into either the ventral striatum or motor cortex resulted in hypokinesia. Moreover, MPEP injected into the olfactory bulb increased the distance mice traveled in the center of the open field arena. With respect to motor coordination on the rotarod, injection of MPEP into the motor cortex and olfactory bulb elicited decreased latency to fall. CONCLUSIONS: Taken together, our data suggest that not only primarily motor neural substrates, but also limbic and sensory structures are involved in mGluR5-mediated motor behavior.

Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein, which underlies the loss of striatal and cortical neurons. Glutamate has been implicated in a number of neurodegenerative diseases, and several studies suggest that the metabotropic glutamate receptor 5 (mGluR5) may represent a target for the treatment of HD. AREAS COVERED: The main goal of this review is to discuss the current data in the literature regarding the role of mGluR5 in HD and evaluate the potential of mGluR5 as a therapeutic target for the treatment of HD. mGluR5 is highly expressed in the brain regions affected in HD and is involved in movement control. Moreover, mGluR5 interacts with htt and mutated htt profoundly affects mGluR5 signaling. However, mGluR5 stimulation can activate both neuroprotective and neurotoxic signaling pathways, depending on the context of activation. EXPERT OPINION: Although the data published so far strongly indicate that mGluR5 plays a major role in HD-associated neurodegeneration, htt aggregation and motor symptoms, it is not clear whether mGluR5 stimulation can diminish or intensify neuronal cell loss and HD progression. Thus, future experiments will be necessary to further investigate the outcome of drugs acting on mGluR5 for the treatment of neurodegenerative diseases.

Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins.

GPCRs represent the largest family of integral membrane proteins and were first identified as receptor proteins that couple via heterotrimeric G-proteins to regulate a vast variety of effector proteins to modulate cellular function. It is now recognized that GPCRs interact with a myriad of proteins that not only function to attenuate their signalling but also function to couple these receptors to heterotrimeric G-protein-independent signalling pathways. In addition, intracellular and transmembrane proteins associate with GPCRs and regulate their processing in the endoplasmic reticulum, trafficking to the cell surface, compartmentalization to plasma membrane microdomains, endocytosis and trafficking between intracellular membrane compartments. The present review will overview the functional consequence of ß-arrestin, receptor activity-modifying proteins (RAMPS), regulators of G-protein signalling (RGS), GPCR-associated sorting proteins (GASPs), Homer, small GTPases, PSD95/Disc Large/Zona Occludens (PDZ), spinophilin, protein phosphatases, calmodulin, optineurin and Src homology 3 (SH3) containing protein interactions with GPCRs.