Glutamate receptors and glutamatergic signalling in the peripheral nerves

Abstract

In the peripheral nervous system, the vast majority of axons are accommodated within the fibre bundles that constitute the peripheral nerves. Axons within the nerves are in close contact with myelinating glia, the Schwann cells that are ideally placed to respond to, and possibly shape, axonal activity. The mechanisms of intercellular communication in the peripheral nerves may involve direct contact between the cells, as well as signalling via diffusible substances. Neurotransmitter glutamate has been proposed as a candidate extracellular molecule mediating the cross-talk between cells in the peripheral nerves. Two types of experimental findings support this idea: first, glutamate has been detected in the nerves and can be released upon electrical or chemical stimulation of the nerves; second, axons and Schwann cells in the peripheral nerves express glutamate receptors. Yet, the studies providing direct experimental evidence that intercellular glutamatergic signalling takes place in the peripheral nerves during physiological or pathological conditions are largely missing. Remarkably, in the central nervous system, axons and myelinating glia are involved in glutamatergic signalling. This signalling occurs via different mechanisms, the most intriguing of which is fast synaptic communication between axons and oligodendrocyte precursor cells. Glutamate receptors and/or synaptic axon-glia signalling are involved in regulation of proliferation, migration, and differentiation of oligodendrocyte precursor cells, survival of oligodendrocytes, and re-myelination of axons after damage. Does synaptic signalling exist between axons and Schwann cells in the peripheral nerves? What is the functional role of glutamate receptors in the peripheral nerves? Is activation of glutamate receptors in the nerves beneficial or harmful during diseases? In this review, we summarise the limited information regarding glutamate release and glutamate receptors in the peripheral nerves and speculate about possible mechanisms of glutamatergic signalling in the nerves. We highlight the necessity of further research on this topic because it should help to understand the mechanisms of peripheral nervous system development and nerve regeneration during diseases.

Keywords: AMPA receptors; NMDA receptors; PNS; Schwann cells; axons; glutamate; metabotropic glutamate receptors; myelination; nerve injury; peripheral nervous system; synaptic signalling.

Figure 1

Scheme showing Glu receptors and Glu release from the peripheral axons. Note that information regarding Glu receptors is based on morphological findings that report presence of receptors on the peripheral axons but do not verify whether these receptors are functional. Information regarding the mechanisms of axonal Glu release is based on the findings in the central nervous system because the mechanisms of Glu release along the axonal shafts in the peripheral nervous system remain unknown. AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AP: action potential; DRG: dorsal root ganglion; Glu: glutamate; KAR: kainate receptor; mGluR: metabotropic Glu receptor; NMDAR: N-methyl-D-aspartate receptor.

Figure 2

Scheme showing Glu receptors and glutamate release from Schwann cells located in the peripheral nerves. Note that several studies report that AMPARs, NMDARs and mGluRs are functional proteins in SCs, but only morphological evidence is available regarding KARs in SCs. Also note that mechanisms of Glu release from SCs are hypothetical as no functional studies are available on this topic. AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Glu: glutamate; KAR: kainate receptor; mGluR: metabotropic Glu receptor; NMDAR: N-methyl-D-aspartate receptor; SC: Schwann cell.

Figure 3

Hypothetical scheme showing glutamatergic signalling in the peripheral nerves (A) between axons and SCs, (B) between axons, and (C) between SCs. Information regarding the glutamate receptors in SCs is based on various findings in cell culture and ex vivo. Information regarding the mechanisms of axonal glutamate release is based on the findings in the central nervous system because the mechanisms of glutamate release along the axonal shafts in the peripheral nervous system remain unknown. Note, that “Axon” represents both myelinated and non-myelinated axons, while “Schwann cell” represents different developmental stages of SC lineage. Akt: Serine/threonine-specific protein kinase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AP: action potential; ErbB2-R: tyrosine kinase epidermal growth factor receptor 2; ERK: extracellular signal-regulated kinase; KAR: kainate receptor; LRP1: low density lipoprotein receptor-related protein 1; mGluR: metabotropic glutamate receptor; NMDAR: N-methyl-D-aspartate receptor; P: phosphorylation; PI3K: phosphoinositide 3-kinase; pink dots: ions or molecules which are co-transported with glutamate; red dots (Glu): glutamate; RSK: ribosomal S6 kinase; S6K: p70 S6 kinase; SCs: Schwann cells. Ion channel represents P2X₇ receptor, TWIK1-related K⁺ channel 1 (TREK-1), bestrophin 1 (BEST1), or any other channel through which glutamate may be released. Transporter represents reversed excitatory amino acid transporter, cystine-glutamate exchanger, or any other transporter through which glutamate may be released.