Group I metabotropic glutamate receptors (mGluR1/5) and neurodegenerative diseases

Abstract

This overview describes how group mGluR1/5 metabotropic glutamate receptors are involved in neurodegenerative diseases; it also touches upon their use as therapeutic targets in animal models. mGluR1/5 are primarily located on the neuronal postsynaptic membrane, where they communicate with two proteins, Gq/11 and Homer, which, in turn, initiate several biochemical cascades. The Gq/11 protein cascade includes Са2+ release from the endoplasmic reticulum (ER) through the inositol trisphosphate receptors (IP3R) and the activation of depot-controlled Са2+ entry. The Gq/11 protein cascade also includes the production of diacylglycerol with subsequent activation of various protein kinases, which, in turn, provide influences on the genome. The Homer protein communicates directly with the NMDA receptors and Shank scaffold proteins, through which it regulates the activity of various protein kinases, including Akt and ERK1/2. The activation of mGluR1/5 triggers long-term depression of glutamatergic transmission through the endocytosis of AMPA receptors, caused by changes in the level of protein phosphorylation and genome activation. It is thought that mGluR1/5 play an important role in the development of neurodegenerative diseases. In Alzheimer's disease, mGluR1/5 acts as a target for the -amyloid peptide. mGluR1/5 antagonists have a neuroprotective effect in transgenic mice with Alzheimer's disease. The pathogenesis of Alzheimer's disease includes increased Са2+ release from the ER due to the pathological activity of mGluR1/5, as well as the influence of mutated presenilin on Са2+ homeostasis in the ER. At the same time, restoration of Са2+ levels in the ER is disrupted by the effect of presenilin on depot-activated Са2+ entry. mGluR5 (but not mGluR1) is being studied as a potential therapeutic target in Parkinson's disease. Numerous studies on rodent and primate models of Parkinson's disease have demonstrated a significant antiparkinsonian effect when mGluR5 antagonists were used. It is thought that the neuroprotective mechanisms of action of mGluR5 antagonists involve limiting the increase in intracellular Са2+ by reducing IP3 and NMDA receptor activation. Huntingtons disease is related to a mutation in the HTT gene and the ability of the mutant huntingtin protein to sensitise IP3 and NMDA receptors, thus triggering Са2+ overload in the neurons. A neuroprotective effect in transgenic mice with Huntingtons disease was achieved by using positive allosteric modulators of mGluR5, capable of selectively activating cascades associated with the Homer protein and triggering Akt activation.

Keywords

• metabotropic glutamate receptors
• alzheimer's disease
• parkinson's disease
• huntington’s disease