Transient receptor potential channels in the context of nociception and pain – recent insights into TRPM3 properties and function

Abstract

Potential harmful stimuli like heat, mechanical pressure or chemicals are detected by specialized cutaneous nerve fiber endings of nociceptor neurons in a process called nociception. Acute stimulation results in immediate protective reflexes and pain sensation as a normal, physiological behavior. However, ongoing (chronic) pain is a severe pathophysiological condition with diverse pathogeneses that is clinically challenging because of limited therapeutic options. Therefore, an urgent need exists for new potent and specific analgesics without afflicting adverse effects. Recently, TRPM3, a member of the superfamily of transient receptor potential (TRP) ion channels, has been shown to be expressed in nociceptors and to be involved in the detection of noxious heat (acute pain) as well as inflammatory hyperalgesia (acute and chronic pain). Current results in TRPM3 research indicate that this ion channel might not only be part of yet unraveled mechanisms underlying chronic pain but also has the potential to become a clinically relevant pharmacological target of future analgesic strategies. The aim of this review is to summarize and present the basic features of TRPM3 proteins and channels, to highlight recent findings and developments and to provide an outlook on emerging directions of TRPM3 research in the field of chronic pain.

Functional expression and pharmacological modulation of TRPM3 in human sensory neurons

“…In recent years, research in rodents has revealed that the cation channel TRPM3 plays a central role in the somatosensory pathway, where it is involved in acute noxious heat sensing and in the development of inflammatory hyperalgesia (Behrendt, ; Vriens et al, ). Moreover, pharmacological inhibition of TRPM3 alleviates pain in a variety of preclinical models in mice and rats (Jia et al, ; Krugel et al, ; Straub et al, ), highlighting the potential of TRPM3 as a target for novel analgesic drugs (Held, Voets, & Vriens, ).…”

Bradykinin-Induced Sensitization of Transient Receptor Potential Channel Melastatin 3 Calcium Responses in Mouse Nociceptive Neurons

“…In native DRG neurons, TRPM3 is co-expressed with a variety of GPCRs and their co-activation can lead to channel inhibition via Gβγ ( Badheka et al, 2017 ; Dembla et al, 2017 ; Quallo et al, 2017 ; Masuho et al, 2018 ; Touhara and MacKinnon, 2018 ; Alkhatib et al, 2019 ). Gβγ binds directly to a sequence of 10 amino acids in exon 17 of TRPM3, and since exon 17 is subject to alternative splicing, this region constitutes an on–off switch for TRPM3 inhibition ( Oberwinkler and Philipp, 2014 ; Behrendt, 2019 ; Behrendt et al, 2020 ). Our finding that BKR activation sensitized subsequent PS responses ( Figure 1 ) appears to contrast with a recent report by Alkhatib et al (2019) showing inhibition of PS-induced calcium responses during concomitant BK application in DRG neurons ( Alkhatib et al, 2019 ).…”

TRPM3_miR-204: a complex locus for eye development and disease

“…Functional expression studies in transfected cells (mostly HEK293) or in cultured primary cells (e.g., β cells, neurons), coupled with electrophysiological (e.g., patch-clamp) recording and fluorometric Ca 2+ imaging techniques have been used to characterize the permeability and gating properties of the central canonical TRPM3-cation pore ('alpha-pore') in the absence or presence of known agonists including PS and/or heat [47,48,50,51,[57][58][59][60][61][62]. Two human kidneyderived TRPM3 isoforms (hTRPM3_1555 and hTRPM3_ 1325 amino-acids) were the first to be characterized as spontaneously or constitutively active Ca 2+ influx channels located in the cell membrane and were inhibited, nonspecifically, by trivalent lanthanides La 3+ and Gd 3+ [108,109].…”

“…In vitro functional expression studies have determined that TRPM3 channels are activated by several structurally unrelated agonists including (1) the endogenous excitatory neurosteroid pregnenolone sulfate, which can also weakly activate TRPM1 channels [51,[57][58][59][60][61][62][63]; (2) cell-membrane phosphoinositol phosphates [64][65][66]; and (3) noxious heat [46][47][48][49][50]. Conversely, they are inhibited by (1) certain clinically approved drugs including nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., mefenamic acid), antibiotics (e.g., voriconazole, which also inhibits TRPM1 channels), sex-steroids (e.g., progesterone), and synthetic drug-like antagonists [40,41,51,61,[67][68][69][70][71][72]; (2) naturally occurring plant-derived secondary metabolites (e.g., citrus flavanones) [73][74][75]; and (3) Gprotein coupled receptor βγ subunits [76][77][78][79].…”