Nociceptor Signalling through ion Channel Regulation via GPCRs

Abstract

The prime task of nociceptors is the transformation of noxious stimuli into action potentials that are propagated along the neurites of nociceptive neurons from the periphery to the spinal cord. This function of nociceptors relies on the coordinated operation of a variety of ion channels. In this review, we summarize how members of nine different families of ion channels expressed in sensory neurons contribute to nociception. Furthermore, data on 35 different types of G protein coupled receptors are presented, activation of which controls the gating of the aforementioned ion channels. These receptors are not only targeted by more than 20 separate endogenous modulators, but can also be affected by pharmacotherapeutic agents. Thereby, this review provides information on how ion channel modulation via G protein coupled receptors in nociceptors can be exploited to provide improved analgesic therapy.

A Review on Chronic Pain in Rheumatoid Arthritis: A Focus on Activation of NR2B Subunit of N-Methyl-D-Aspartate Receptors

“…NMDAR can be found in the soma of primary afferent neurons in the dorsal root ganglia (DRG) (16-18), peripheral nerves terminals of primary afferent fibres in skin and muscle (19,20) and trigeminal ganglion neurons (18,19). Furthermore, it is also broadly distributed at the level of lamina I-II in the spinal cord (21) and several brain regions involved in the ascending and descending systems (21)(22)(23)(24)(25).…”

“…GPCRs include muscarinic, Review Article | NR2B subunit of NMDAR in rheumatoid arthritis lysophosphatidic acid (LPA), and metabolic glutamate receptor 5 (mGluR5) receptors (24). These receptors may either amplify neuronal excitability or mediate the suppressive effects that diminish the neuronal excitability (21). There are several pathways by which GPCRs can activate the NR2B subunit.…”

“…This ligand stimulates Src kinase phosphorylation at C-terminus of the NR2B subunit. Furthermore, CAKβ also acts by inhibiting the intramolecular networks that cause low-activity condition of Src kinase to ensure that activation can take place (21,33). Eventually, this pathway leads to the upregulation of the NR2B subunit of NMDAR, as shown in a rat model of inflammatory hyperalgesia (3).…”

“…For example, transient receptor potential (TRP) channels such as TRPV1-4 and TRPM3 detect noxious heat sensation whereas TRPA1, TRPC5 and TRPM8 are associated with noxious cold temperatures. TRPA1 and TRPV4 subunits detect noxious mechanical signals while TRPA1, TRPV1, TRPV3, TRPM8 and TRPC3 are involved in the transmission of itch sensation (21). These ion channels are heavily expressed on Aδ-and C-fibres.…”

“…The binding of ανβ3-and α5β1-type integrins to their receptors can activate the SFKs. This activation takes place following the CAKβ activation that provides the SH2 docking sites on the C-terminal of NR2B subunit (4,21,33). The pro-inflammatory effect of integrin is also mediated via its activation of other signalling proteins, including RACK1 and MAPK following the Ras pathway.…”