The Molecular Pharmacology and Cell Biology of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are of fundamental importance in the brain. They are responsible for the majority of fast excitatory synaptic transmission, and their overactivation is potently excitotoxic. Recent findings have implicated AMPARs in synapse formation and stabilization, and regulation of functional AMPARs is the principal mechanism underlying synaptic plasticity. Changes in AMPAR activity have been described in the pathology of numerous diseases, such as Alzheimer’s disease, stroke, and epilepsy. Unsurprisingly, the developmental and activity-dependent changes in the functional synaptic expression of these receptors are under tight cellular regulation. The molecular and cellular mechanisms that control the postsynaptic insertion, arrangement, and lifetime of surface-expressed AMPARs are the subject of intense and widespread investigation. For example, there has been an explosion of information about proteins that interact with AMPAR subunits, and these interactors are beginning to provide real insight into the molecular and cellular mechanisms underlying the cell biology of AMPARs. As a result, there has been considerable progress in this field, and the aim of this review is to provide an account of the current state of knowledge.

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

“…Finally, altered calcium signaling has been proposed as a unifying hypothesis of schizophrenic pathology (Lidow 2003), and the calcium permeability of AMPA receptors is determined by the presence or absence of GluR2 (Dingledine et al 1999;Jayakar and Dikshit 2004). This elevation in GRIA2 subunit mRNA is also important because GluR2 subunit expression in AMPA receptors renders AMPA receptor impermeable to calcium (Dingledine et al 1999;Palmer et al 2005). Therefore, increasing GRIA2 expression and decreasing calcium permeability of AMPA receptors expressed in the DLPFC is also a potential mechanism of action for APDs.…”

“…Alternative splicing in the extracellular N-terminal region of the fourth transmembrane domain yields variants termed "flip" and "flop" for each subunit (Sommer et al 1990). Stoichiometry of the functional ionophore is controlled by the expression levels of individual subunits which affect several properties of the mature receptor including receptor trafficking and cellular physiology (Koike et al 2000;Mosbacher et al 1994;Palmer et al 2005). Therefore altered expression of AMPA receptor subunit or splice variants might underlie disturbances in glutamatergic neurotransmission in schizophrenia patients.…”

“…AMPA receptors are tetrameric structures assembled from four subunits GRIA1-4, each of which exists in splice variant forms (Palmer et al 2005). Alternative splicing in the extracellular N-terminal region of the fourth transmembrane domain yields variants termed "flip" and "flop" for each subunit (Sommer et al 1990).…”

Regulation of AMPA receptors and synaptic plasticity

“…The GluR4 subunit is present in lower amounts throughout the CNS, except in the reticular thalamic nuclei and the cerebellum, where this subunit is also abundant (Petralia and Wenthold, 1992;Martin et al, 1993;Spreafico et al, 1994). The expression of AMPAR subunits is also differentially regulated during development Palmer et al, 2005b;Talos et al, 2006), and although they are regarded as neuronal receptors, they have also been detected in glial cells (Gallo and Russell, 1995;Janssens and Lesage, 2001;Lin and Bergles, 2004).…”

Autoimmune Encephalitides

“…[163]. Located in hippocampus and outer cortex, olfactory regions, lateral septum, basal ganglia, and amygdala [166], AMPAR trafficking plays a role in long-term potentiation (LTP) important in long-lasting increase in signal transmission between neurons forming the substrate for memory and learning. Brain-derived neurotrophic factor (BDNF) activates the kinase, mechanistic target of rapamycin (mTOR) that regulates GluR1 expression required for memory formation.…”