Many neurotransmitters mediate their actions by acting on both ligand-gated ion channels and G-protein coupled receptors. Using a specific neurotransmitter describe the similarities and differences that this neurotransmitter has on its two receptor types.

 

Glutamate is the most abundant neurotransmitter in the CNS, binding to specific receptors for ionotropic communication as well as G-protein coupled receptors to activate metabotropic communication in neurons.

There are several types of Ionotropic and Metabotropic glutamate receptors. The ionotropic receptors are voltage gated ion channels which are directly activated by the binding of glutamate to allow passage of ions across the plasma membrane. The metabotropic glutamate receptors bind glutamate to initialize a series of intracellular signalling events with are relatively complex and have a multitude of downstream effects.

In the case of ionotropic glutamate receptors (iGluRs) they are categorized further into four distinct classes:-

GluA (AMPA, 2-amino-3-3- hydroxy-5-methyl-isoxazol-4-yl propanoic acid), GluK (kainate), GluN (NMDA, N-Methyl-D-aspartic acid), and GluD (δ) receptors. These all mediate influx and outflux of cations, primarily relatively large amounts of Sodium in and smaller amounts of Potassium out. Each receptor is named in accordance with the ligand with which they bind that does not show any affinity for the other types. GluN and GluA are heterotetrameric, comprised of four non-identical subunits. GluK can be heterotetrameric or homotetrameric.

Ionotropic mediated communication is rapid and once glutamate binds to the receptor causing it to open, it can induce a large flow of charge across the membrane even if the transmembrane voltage is small (Barco et al., 2006). Once the receptor binds glutamate, it undergoes a conformational change allowing either influx of sodium ions or outflux of potassium ions, which causes membrane depolarization of the post-synaptic neuron. Sufficient summation of membrane depolarization due to combined activity of glutamate-receptor binding can initialize transmission of an action potential in an all or nothing response, which is transmitted along the axon.

The GluN receptor has somewhat bizarre behaviour in that it is only active when the membrane in which it resides is already depolarized, as at resting potentials it is blocked by magnesium. This receptor is highly expressed () on CNS neurons and plays a role in neural plasticity, memory, learning and neurogenesis.

 

Glutamate mediated metabotropic communication relies on G-protein coupled receptors and are relatively slow but can initiate a cascade of subsequent downstream effects in addition to being able to multiply the initial signal by many orders of magnitude, whereas ion channels have the sole role of ion influx or outflux. These receptors are bound on one of their intracellular domains to a G-protein which upon activation substitutes GDP for GTP to become active and subsequently induces an enzymatic cascade. This can have a multitude of different effects such as opening of an ion channel or altering the channels response upon a transmembrane voltage change (Barker, R.A et al. 2018). Or altering regulation of gene transcription and protein synthesis as the signal cascade interacts with the DNA-protein complexes which govern gene expression.

 

G-protein coupled glutamate receptors or mGluRs are split into three main groups each containing between two and four subtytpes. They are all homodimeric, comprised of two identical subunits and are grouped based on their downstream signalling mechanisms. Their grouping is dependant upon which exclusive ligand they can be activated by. In the case of group1 mGluRs this is DHPG, Group2 bind DCG-IV and Group3 binds L-AP4.

Group1 utilises phospholipase C in their signal pathways and is located on the post-synaptic neuron. Once activated they can induce a variety of subsequent effects such as excitatory, stimulating further release of glutamate by the presynaptic neuron or increasing inhibitory post-synaptic potentials. Group2 and Group 3  mGluRs use adenylyl cyclase signal transduction and are predominantly found on presynaptic neurons.

mGluR activation primarily affects gene expression and protein synthesis in order to excite the glutamate cells, regulate the level of neurotransmitter release or synaptic plasticity. Once glutamate binds with the receptor, the binding causes an alteration in the receptor proteins intracellular tertiary structure. This leads to a signal cascade intracellular sequences which are relatively complex and lead to cellular activity change.

Both metabotropic and ionotropic receptors in the CNS undergo a conformational change upon binding glutamate. With ionotropic receptors this results in a channel opening which traverses the membrane whereas with metabotropic receptors the conformational change only occurs on the intramembrane side.

 

Barco, A., Bailey, C.H., Kandel, E.R. (2006) Common molecular mechanisms in explicit and implicit memory. Journal of Neurochemistry. 97(6):1520–1533

 

Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: Workshop Summary. (2011) Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders.

 

Barker, R.A., Cicchetti, F., Robinson, S.J. (2018) Neuroanatomy and Neuroscience at a Glance. Wiley Blackwell.