Glutamate, glutamate receptors, and downstream signaling pathways

Int J Biol Sci. 2013 Sep 22;9(9):948-59. doi: 10.7150/ijbs.6426. eCollection 2013.

Abstract

Glutamate is a nonessential amino acid, a major bioenergetic substrate for proliferating normal and neoplastic cells, and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways. Glutamate signaling activates a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in chronic disabling brain disorders such as Schizophrenia and neurodegenerative diseases like Alzheimer's, Parkinson's, and multiple sclerosis. In this review, we discuss the structural and functional relationship of mGluRs and iGluRs and their downstream signaling pathways. The three groups of mGluRs, the associated second messenger systems, and subsequent activation of PI3K/Akt, MAPK, NFkB, PLC, and Ca/CaM signaling systems will be discussed in detail. The current state of human mGluR1a as one of the most important isoforms of Group I-mGluRs will be highlighted. The lack of studies on the human orthologues of mGluRs family will be outlined. We conclude that upon further study, human glutamate-initiated signaling pathways may provide novel therapeutic opportunities for a variety of non-malignant and malignant human diseases.

Keywords: GRM1a; Glutamate; iGluR; mGluR; signaling..

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Calcium / metabolism
  • Calcium Signaling
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Glutamic Acid / metabolism*
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • NF-kappa B / physiology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Glutamate / chemistry
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism*
  • Sequence Alignment
  • Signal Transduction*
  • Type C Phospholipases / metabolism
  • Type C Phospholipases / physiology

Substances

  • NF-kappa B
  • Receptors, G-Protein-Coupled
  • Receptors, Glutamate
  • Glutamic Acid
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Type C Phospholipases
  • Calcium