NMDA Receptors are not Alone: Dynamic Regulation of NMDA Receptor Structure and Function by Neuregulins and Transient Cholesterol-Rich Membrane Domains Leads to Disease-Specific Nuances of Glutamate- Signalling

Abstract

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.

Polymodal Regulation of NMDA Receptor-Channels

“…The cytoplasmic C-terminus harbours numerous sites for interaction with intracellular proteins. 18,52 The pore-lining loop (P) of both subunits harbours an asparagine residue at a position homologous to the Q/R site of AMPA receptors. The RNA editing of the Q/R site controls Ca 2+ and Mg 2+ permeability which affects single channel conductance and alters the current-voltage (I-V) relation of AMPA receptors.…”

Combined Low Calcium and Lack Magnesium Is a Risk Factor for Motor Deficit in Mice

“…28) The neuroprotective effect of Mg is mediated via a reduction in pre-synaptic release of the neurotransmitter glutamate 29) or a blockade of NMDA receptors. 30) In a variety of experimental models of PD, many NMDA receptor blockers have shown anticataleptic activity, including dizocilpine, phencyclidine, memantine.…”

Pharmacological evaluation of catalepsy in low calcium and/or magnesium deficient feeding mice

“…The NMDA receptors are thought to be responsible for this excitotoxicity and the subsequent downstream events like neuroinflammation and apoptosis, and thus have been implicated in many important human pathologies ranging from ALS to Alzheimer's disease, PD, depression, epilepsy, trauma and schizophrenia [25]. Mg's neuroprotective effect is mediated via a reduction in the presynaptic release of the neurotransmitter glutamate [26] or blockade of NMDA receptors [27].…”