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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 400, Issue 7

Issues

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

Marc Behrendt
  • Corresponding author
  • Experimental Pain Research, Heidelberg University, Medical Faculty Mannheim, CBTM, Tridomus, Building C, Ludolf-Krehl-Straße 13-17, D-68167 Mannheim, Germany
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Published Online: 2019-03-23 | DOI: https://doi.org/10.1515/hsz-2018-0455

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.

Keywords: analgesia; G-protein coupled receptors; heat; hyperalgesia; opiods; TRP ion channels

Introduction

Acute pain serves an important physiological function as an alert signal that leads to almost instantaneous protective reactions after contact with potential harmful stimuli as well as preservation of injured tissue. Ongoing (chronic) pain, a condition for which only few treatments are available, extends beyond the time of healing and has lost its protective function after structural reorganization of nociceptive pathways (Kuner and Flor, 2016). In peripheral nerve terminals of nociceptor neurons (weakly myelinated Aδ-fibers and non-myelinated C-fibers), stimuli-sensitive molecules like cell surface receptors and ion channels are expressed. Their activation can lead to sodium and calcium ion influx, depolarization and action potential generation, modulating information sending towards the central nervous system. For some of these receptors and ion channels, roles in acute and chronic pain have been suggested, like for some members of the heterogenous group of transient receptor potential (TRP) channels (Julius, 2013; Gonzalez-Ramirez et al., 2017; Moran and Szallasi, 2018).

TRP channels are molecular sensors and signal transducers of a variety of chemical and physical stimuli, e.g. camphor, mustard oil and menthol as well as heat, cold and low pH (Flockerzi and Nilius, 2014). The first identified (Caterina et al., 1997) and probably one of the most investigated members of this ion channel family is the polymodal receptor TRPV1, which is activated by heat, capsaicin (the ‘hot’ component of chili pepper), piperine (in black pepper) and many other substances (Bevan et al., 2014). The findings that TRPV1-positive neurons are essential for the sensing of noxious heat and that TRPV1-deficient mice do not develop inflammatory heat hyperalgesia has led to an intensive search for clinically useful TRPV1-targeting analgesics (Moran and Szallasi, 2018). However, none of the identified drug candidates are in clinical use, because TRPV1 inhibition resulted (i) in core body temperature increase, (ii) compromised noxious heat reactions and (iii) no or limited therapeutic effects (Vriens and Voets, 2018).

In 2011, another member of the TRP channel family was presented as a nociceptive channel involved in the detection of noxious heat and inflammatory hyperalgesia: transient receptor potential melastatin 3 (TRPM3) (Vriens et al., 2011).

TRPM3 – basic features

The first two research articles introducing TRPM3 appeared in 2003 and detailed an ion channel expressed in human kidney and brain that is permeable to mono- and divalent cations (including Ca2+) and can be activated by hypotonic extracellular solution (Grimm et al., 2003; Lee et al., 2003). This was, in comparison to the other TRP channels, a rather late appearance, TRPV1, for instance, had already been introduced in 1997 (Caterina et al., 1997). A recent (November 2018) PubMed search revealed that TRPM3 has been mentioned in fewer publications than the other members of its protein family. Nevertheless, fascinating results and developments within the last few years have led to interesting questions and new ideas regarding TRPM3. Together with the availability of potent genetic and pharmacological tools, these findings opened untrodden routes towards unraveling the physiological role of TRPM3 and its potential in having diagnostic and therapeutic value. The aim of this review is to summarize the basic features of TRPM3 channels and to highlight recent findings showing its possible functional role in nociception and pain.

Genomic organization, alternative splicing and expression

The mouse Trpm3 gene contains 28 exons within 870.77 kb on chromosome 19 B, with exons 1, 2 and 3 being separated by large introns (Oberwinkler and Philipp, 2014). The existence of alternative promoters as well as transcription start sites upstream of these exons has been suggested and three classes of splice variants have been described, starting either with exon 1 (TRPM3α), exon 2 (TRPM3β) or with exonic sequences downstream of exon 2 (Oberwinkler and Philipp, 2014). Exons 1 and 2 seem to be expressed in a mutually exclusive way as no cDNA clones carrying both exons have been described (Oberwinkler and Philipp, 2014). In general, the organization of the TRPM3 gene seems to be conserved in mammals and a large number of splice variants have been identified in mice and humans (Bennett et al., 2014; Oberwinkler and Philipp, 2014; Suzuki et al., 2016). However, the amino acid sequences of endogenous proteins can be different from the ones predicted from cDNA sequences, as for example, described for TRPV6 (Fecher-Trost et al., 2013), and the amino acid sequences of endogenously expressed TRPM3 proteins have not yet been resolved.

Currently, only a few of the large number of TRPM3 splice variants have been characterized: while TRPM3α1 channels are permeable to monovalent but hardly to divalent cations, TRPM3α2 (differing only in the presumed pore region sequence from TRPM3α1) shows a high permeability for divalent cations like Mg2+ and Ca2+ (Oberwinkler et al., 2005). TRPM3α7, which lacks 54 nucleotides in exon 13 in comparison to TRPM3α2, shows reduced cell surface localization and is not permeable to ions, but can instead act as a regulatory subunit within multimeric TRPM3 channels (Frühwald et al., 2012). TRPM3α5, which lacks exon 17 of the TRPM3α2 sequence, is resistant to the inhibitory effect of activated G-protein coupled receptors that are effective on exon 17-positive variants (Behrendt et al., 2014). The exon compositions of the characterized mouse TRPM3 splice variants described are given in Figure 1A . Importantly, in many studies employing heterologously overexpressed TRPM3, the highly Ca2+-permeable mouse splice variant TRPM3α2 has been utilized. Therefore, this is the best-characterized isoform and results obtained from endogenous, Ca2+-permeable, mouse TRPM3 isoforms with unknown splice variant composition patterns are often compared to results generated with TRPM3α2. The role of endogenously expressed TRPM3 variants with little permeability for divalent cations (e.g. TRPM3α1) has not yet been elucidated (Oberwinkler and Philipp, 2014).

Properties and functions of TRPM3 ion channels. (A) TRPM3 isoforms. The mouse Trpm3 gene contains 28 exons and more than 20 splice variants have been identified. The exon compositions for the mouse variants mTRPM3α1 [1721 amino acids (aa)], mTRPM3α2 (1709 aa), mTRPM3α5 (1699 aa) and mTRPM3α7 (1691 aa), which have been characterized as described in the text, are shown. The exon compositions for the mouse variants mTRPM3α3 (1721 aa), mTRPM3α4 (1711 aa), mTRPM3α6 (1734 aa) and mTRPM3β1 (1719 aa) (Oberwinkler et al., 2005; Frühwald et al., 2012; Oberwinkler and Philipp, 2014) as well as the human variant hTRPM31325 (1325 aa) (Grimm et al., 2003; Oberwinkler et al., 2005) are shown for comparison and to present a more detailed picture of TRPM3 alternative splicing. Black bars; exons or exon parts. Thin lines; no exons or exon parts. (B) TRPM3 proteins. The best-characterized TRPM3 isoform is mouse (m)TRPM3α2 and mTRPM3α2 proteins are supposed to comprise six membrane spanning domains (black rectangles) as well as cytosolic N- and C-termini. The N-terminus is composed of calmodulin binding sites (CaM) and a domain indispensable for channel function (ICF). The C-terminus includes a TRP motif (TRP) as well as a coiled-coil sequence and the pore loop of the central pore is located between the fifth and sixth transmembrane domains. (C) TRPM3 channels. TRPM3 channels (blue rectangles with blue lines) are supposed to form tetramers in the plasma membrane of cells. Pregnenolone sulfate (PregS) and heat open (+) the classical, central pore (straight red arrow) and CIM0216 as well as the combination of PregS and clotrimazole (Clotri) open (+), in addition, an alternative permeation pathway (zigzag red arrows). Activation of Gαi/o-protein coupled receptors (GiPCRs) results in separation of G-protein α (Gα) and βγ (Gβ and Gγ) subunits and subsequently inhibition (−) of TRPM3 channels via Gβγ. Phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol trisphosphate (PIP3) are positive modulators (+) of TRPM3. Dashed lines indicate cytosolic protein regions. S1–S4; transmembrane domains 1–4. S5,S6; transmembrane domains 5–6. Morphine, DAMGO; activators of μ-opioid receptors. Baclofen; activator of GABAB receptors. PYY; activator of neuropeptide Y receptors Y2. (D) TRPM3 functions. TRPM3 channels (blue rectangles) at the endings of afferent nerve fibers (red lines) in the skin are activated (+) by heat, PregS, CIM0216 as well as the combination of PregS and clotrimazole (Clotri) inducing nocifensive behavior in mice. This behavior can be suppressed (−) by morphine, DAMGO, baclofen, PYY, primidone, isosakuranetin and liquiritigenin. CIM0216 induced (+) CGRP (calcitonin gene-related peptide) release (C) can be antagonized (−) with isosakuranetin.
Figure 1:

Properties and functions of TRPM3 ion channels.

(A) TRPM3 isoforms. The mouse Trpm3 gene contains 28 exons and more than 20 splice variants have been identified. The exon compositions for the mouse variants mTRPM3α1 [1721 amino acids (aa)], mTRPM3α2 (1709 aa), mTRPM3α5 (1699 aa) and mTRPM3α7 (1691 aa), which have been characterized as described in the text, are shown. The exon compositions for the mouse variants mTRPM3α3 (1721 aa), mTRPM3α4 (1711 aa), mTRPM3α6 (1734 aa) and mTRPM3β1 (1719 aa) (Oberwinkler et al., 2005; Frühwald et al., 2012; Oberwinkler and Philipp, 2014) as well as the human variant hTRPM31325 (1325 aa) (Grimm et al., 2003; Oberwinkler et al., 2005) are shown for comparison and to present a more detailed picture of TRPM3 alternative splicing. Black bars; exons or exon parts. Thin lines; no exons or exon parts. (B) TRPM3 proteins. The best-characterized TRPM3 isoform is mouse (m)TRPM3α2 and mTRPM3α2 proteins are supposed to comprise six membrane spanning domains (black rectangles) as well as cytosolic N- and C-termini. The N-terminus is composed of calmodulin binding sites (CaM) and a domain indispensable for channel function (ICF). The C-terminus includes a TRP motif (TRP) as well as a coiled-coil sequence and the pore loop of the central pore is located between the fifth and sixth transmembrane domains. (C) TRPM3 channels. TRPM3 channels (blue rectangles with blue lines) are supposed to form tetramers in the plasma membrane of cells. Pregnenolone sulfate (PregS) and heat open (+) the classical, central pore (straight red arrow) and CIM0216 as well as the combination of PregS and clotrimazole (Clotri) open (+), in addition, an alternative permeation pathway (zigzag red arrows). Activation of Gαi/o-protein coupled receptors (GiPCRs) results in separation of G-protein α (Gα) and βγ (Gβ and Gγ) subunits and subsequently inhibition (−) of TRPM3 channels via Gβγ. Phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol trisphosphate (PIP3) are positive modulators (+) of TRPM3. Dashed lines indicate cytosolic protein regions. S1–S4; transmembrane domains 1–4. S5,S6; transmembrane domains 5–6. Morphine, DAMGO; activators of μ-opioid receptors. Baclofen; activator of GABAB receptors. PYY; activator of neuropeptide Y receptors Y2. (D) TRPM3 functions. TRPM3 channels (blue rectangles) at the endings of afferent nerve fibers (red lines) in the skin are activated (+) by heat, PregS, CIM0216 as well as the combination of PregS and clotrimazole (Clotri) inducing nocifensive behavior in mice. This behavior can be suppressed (−) by morphine, DAMGO, baclofen, PYY, primidone, isosakuranetin and liquiritigenin. CIM0216 induced (+) CGRP (calcitonin gene-related peptide) release (C) can be antagonized (−) with isosakuranetin.

Human TRPM3 splice variants have been identified using cDNAs from kidney (Lee et al., 2003), brain and kidney (Grimm et al., 2003) as well as lenses (Bennett et al., 2014). Interestingly, a mutation in the exonic sequence of TRPM3 is proposed to affect several splice variants and to underlie inherited cataract and glaucoma (Bennett et al., 2014). Recently, investigating distinct human isoforms, Suzuki and colleagues could show that all tested variants were inhibited by diclofenac, but with different potencies (Suzuki et al., 2016). Presently, I am unaware of quantitative data of human TRPM3 splice variant distribution, but such data obtained with mouse tissue is available (Frühwald et al., 2012). A detailed analysis of 144 independent full-length TRPM3 variants of the choroid plexus identified 17 novel variants and revealed six different regions that are subject to alternative splicing. The frequency of splice events within these regions (encoded by exons 8, 13, 15, 17, 20 and 24) ranged from 4.9% (exon 20) to 95.1% (exon 24) (Frühwald et al., 2012). More recently, the same group introduced an improved, simple but reliable reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method for quantifying splice variant ratios in single samples, increasing the prospects of deeper insights into TRPM3 splice variant distribution in the context of nociception and pain (Camacho Londono and Philipp, 2016).

Endogenous (Ca2+-permeable) TRPM3 channels have been identified in a variety of cell types using a variety of different methods. TRPM3 expression is seen in the cells of the choroid plexus (Oberwinkler et al., 2005), pancreatic islets (Wagner et al., 2008), vascular smooth muscle (Naylor et al., 2010) and dorsal root ganglia (Staaf et al., 2010). [For an overview of TRPM3 expression see (Oberwinkler and Philipp, 2014).] The functional characterization of heterologously and endogenously expressed TRPM3 proteins has predominantly aimed at channels located at the cell surface, e.g. utilizing Ca2+-imaging and whole-cell patch-clamping approaches. One study, investigating the subcellular localizations of TRP channels in human fetal retinal pigment epithelium cells suggested that TRPM3 is located at the base of the primary epithelium and at apical tight junctions (Zhao et al., 2015). Recently, another study revealing mechanistic details about the regulation of TRPM8 transport to the cell surface included results that indicate a role for the vesicle-associated membrane protein 7 (VAMP7) in determining TRPM3 abundance at the plasma membrane (Ghosh et al., 2016). However, little is known about subcellular localization of TRPM3 proteins, their trafficking dynamics, putative interaction partners nor their potential intracellular role.

Functions, structure and interaction partners

Endogenous TRPM3 channels were first characterized in the rat insulinoma cell line Ins1 and in mouse pancreatic β-cells, whereby application of TRPM3 activators followed by biophysical analysis of ion channel properties verified its expression (Wagner et al., 2008). The results of this study suggested a role of TRPM3 in insulin secretion regulation, mainly because stimulation of pancreatic β-cells with the TRPM3 agonist pregnenolone sulfate (PregS) increased glucose-induced insulin release (Wagner et al., 2008; Klose et al., 2011). However, the resting blood glucose level in TRPM3-deficient mice is normal, indicating no or only a minor role of TRPM3 in the regulation of blood glucose levels under non-challenging conditions and/or compensatory mechanisms (Vriens et al., 2011). Another study investigating the function of TRPM3 in pancreatic β-cells further showed that these channels are highly permeable for zinc ions under physiological conditions and a role in zinc uptake regulation was proposed (Wagner et al., 2010).

Endogenous TRPM3 has also been investigated in vascular smooth muscle cells, showing constitutive channel activity and indicating a relevance in cell proliferation as well as blood vessel contraction (Naylor et al., 2010). Interestingly, a recent study showed that in sport-hunting dogs, genes related to neuronal, muscular and cardiovascular functions are under strong selective pressure and that TRPM3 is one gene that is highly associated with increased racing speed (Kim et al., 2018). The possible role of TRPM3 in vascular biology has prompted speculation that TRPM3 might be involved in establishing and maintaining the superior athletic ability of these dogs by optimizing blood flow to skeletal muscle. TRPM3 has also been identified in distinct cell types of the eye, inter alia in the ciliary body and in Müller cells, where one suggested function is a contribution to pupillary light responses (Hughes et al., 2012). In addition, TRPM3 is also expressed in human lens as described already and a mutation in the exonic sequence was found to create an alternative translation initiation site probably resulting in malfunctioning TRPM3 proteins (Bennett et al., 2014).

In order to fully understand all the functions of a protein in detail and to become able to monitor and modulate them for scientific, diagnostic and therapeutic purposes, detailed structural information is required. The first high-resolution structure of TRP channels was obtained at 3.4 Å resolution by electron cryo-microscopy for TRPV1 in 2013 (Cao et al., 2013; Liao et al., 2013). This was followed in 2015 by the structural determination of TRPA1 (Paulsen et al., 2015) and subsequently for members of the TRPM-melastatin subfamily: TRPM2 (Huang et al., 2018; Zhang et al., 2018), TRPM4 (Guo et al., 2017; Autzen et al., 2018; Duan et al., 2018b), TRPM7 (Duan et al., 2018a) and TRPM8 (Yin et al., 2018). For full-length TRPM3 no detailed structural information is available currently, but it is likely that most TRPM3 splice variants contain six membrane-spanning domains with cytosolic N- and C-termini. Figure 1B gives an overview about protein topology, domains and motifs. TRPM3 proteins are supposed to form tetrameric quaternary structures similar to other TRP channels. It has been shown that identical and different TRPM3 splice variants as well as TRPM3 and TRPM1 proteins can form multimers (Hoffmann et al., 2010; Lambert et al., 2011; Frühwald et al., 2012).

Besides its ability to form homo-multimers, TRPM3 proteins have also been shown to interact with other molecules. One of these molecules is the small, soluble, cytosolic Ca2+-binding protein calmodulin, which was found to bind with different affinities to several sites on the TRPM3 N-terminus to mediate the modulation of channel activity by intracellular Ca2+ (Holakovska et al., 2012; Przibilla et al., 2018). Similarly, the Ca2+-binding protein S100A1 interacts with TRPM3 (Holakovska et al., 2012). Moreover, membrane phosphatidylinositol phosphates (PIPs) bind to TRPM3 proteins to increase channel activity with the potency order PI(3,4,5)P3>PIP2>>PI(4)P (Holendova et al., 2012; Badheka et al., 2015; Toth et al., 2015). For reconstituted TRPM3 proteins in planar lipid bilayers the presence of PI(4,5)P2 is a prerequisite for channel activation by PregS but not by nifedipine, another chemical TRPM3 activator (Uchida et al., 2016). Finally, G-protein βγ subunits, released by activation of G-protein coupled receptors, form complexes with TRPM3 and inhibit channel activity in sensory neurons (Badheka et al., 2017; Dembla et al., 2017b; Quallo et al., 2017).

Taken together, regulation of TRPM3 activity has been shown to occur at different levels, including transcription, alternative splicing, subcellular localization as well as interaction with regulatory molecules.

Permeation and basic pharmacology – activation

TRPM3 proteins form non-selective cation channels, which show a rather small but significant basal activity (Grimm et al., 2003; Lee et al., 2003; Oberwinkler et al., 2005; Naylor et al., 2010). The long-pore variant (TRPM3α1) shows little permeability for divalent ions (Oberwinkler et al., 2005), while short-pore variants (e.g. TRPM3α2) can be highly permeable to Ca2+ and Zn2+ (Drews et al., 2010; Wagner et al., 2010). This biophysical characteristic distinguishes TRPM3 from its closest homolog TRPM1, which is blocked by Zn2+ and offers a possibility to differentiate between TRPM3 and TRPM1 (Lambert et al., 2011; Schneider et al., 2015). A quantitative description of the permeability profile of TRPM3α2 channels is given in (Wagner et al., 2010).

The availability of selective and potent pharmacological tools is a prerequisite to investigate molecular and cellular properties and functions of ion channels in detail. D-erythro-sphingosine, which is endogenously produced in the human body, was described as TRPM3 activator (Grimm et al., 2005). Subsequently, the endogenous steroid PregS was shown to activate TRPM3 rapidly and reversibly and it was used to identify and investigate TRPM3 channels in pancreatic β-cells (Wagner et al., 2008). The structural properties of PregS important for TRPM3 activation have recently been characterized (Drews et al., 2014). The dihydropyridine and L-type calcium channel blocker nifedipine can also activate TRPM3 (Wagner et al., 2008) and, interestingly, co-application of PregS together with nifedipine results in supra-additive activation of TRPM3, indicating distinct binding sites (Drews et al., 2014). In addition, a nifedipine analogue (De-nitro-nifedipine) showed strong agonistic potency at concentrations >25 μm when solely applied, but resulted in a strong, supra-linear activity potentiation at concentrations as low as 3.5 μm when co-applied with PregS (Behrendt et al., 2015). The fungicide clotrimazole was identified as a modulator of TRPM3 and, when applied together with PregS, is able to open a second (‘omega-like’) pore separate from the central pore in wild type TRPM3 channels (Vriens et al., 2014). A very recent follow-up study investigated structural requirements in the TRPM3 protein further for this alternative ion conduction pathway (Held et al., 2018). The most potent TRPM3 agonist available today is the small synthetic substance CIM0216, which opens both conduction pathways and was used to reveal a role of TRPM3 channels in peptide release from pancreatic islets and sensory nerve endings (Held et al., 2015a).

Apart from chemical substances, TRPM3 can also be activated by hypotonic solutions (Grimm et al., 2003). Although the underlying mechanism of activation is not clear, hypotonic activation of TRPM3 may serve a mechanical sensor role in rat ductus arteriosus smooth muscle (Aoki et al., 2014), human periodontal ligament and mouse osteoblastic cells (Son et al., 2015, 2018). TRPM3 activity is also sensitive to voltage as well as heat (Vriens et al., 2011), adding this channel to the group of temperature-sensitive TRP channels or ‘ThermoTRPs’ (Patapoutian et al., 2003; Vriens et al., 2014). However, in contrast to TRPM3 investigated in cellular systems, TRPM3 incorporated into planar lipid bilayers does not show a strong intrinsic temperature sensitivity but can be opened in the presence of PIP2 (Uchida et al., 2016). TRPM3 ion channel characteristics including permeation and activity modulation are displayed in Figure 1C.

TRPM3 – role(s) in the somatosensory system

TRPM3 is functionally expressed in a subset (~60%) of dorsal root ganglia (DRG) and trigeminal ganglia (TG) small-diameter sensory neurons in mice (Vriens et al., 2011). There, its activation by PregS accounts for nocifensive paw licking and lifting observed in response to intraplantar injection of this neuroactive steroid in wild type but not in TRPM3-deficient mice (Vriens et al., 2011). TRPM3-deficient mice do not develop heat hyperalgesia after the pro-inflammatory complete Freund’s adjuvant (CFA) challenge, nor show aversion to drinking PregS-containing water and their avoidance of noxious heat, but not cold or mechanical stimuli is reduced (Vriens et al., 2011). Interestingly, while PregS at concentrations as low as 100 nm, which is in the range found in blood plasma (Harteneck, 2013), does not activate TRPM3 at room temperature, it evokes robust responses at body temperature 37°C, indicating that PregS could indeed be an endogenous agonist of TRPM3 in mice (Vriens et al., 2011). This temperature-dependent increase in PregS potency was not confirmed for a human TRPM3 splice variant (Majeed et al., 2012), but differences in exon sequences and composition may explain this discrepancy.

Heat alone cannot activate the second ‘omega-pore’ permeation pathway in TRPM3 channels, but increasing the temperature amplifies the PregS-clotrimazole-induced extra inwardly rectifying (Na+) current (Vriens et al., 2014). This leads to increased excitation of sensory neurons together with increased action potential firing and aggravated pain behavior after intraplantar injection in wild type but not TRPM3-deficient mice (Vriens et al., 2014). The endogenous opener of the alternative conduction pathway, or both pathways, in TRPM3 is not known, but it is tempting to speculate that it could be an inflammatory mediator. Moreover, the identification of a selective blocker of this ‘side door’ would complement existing blockers of the central pore further establishing TRPM3 as an attractive and auspicious target for new analgesics (Liman, 2014). Shortly after the demonstration of the second pore in TRPM3 channels, the small synthetic compound CIM0216 was shown to open both ionic conduction pathways in TRPM3 channels with high selectivity and potency and in a temperature-dependent manner (Held et al., 2015a). Furthermore, CIM0216 injection into the skin of mice resulted in nocifensive behavior of wild type but not TRPM3-deficient animals and application of PregS or CIM0216 to isolated hind paw skin led to TRPM3-dependent release of the neuropeptide CGRP from nerve terminals and neurogenic inflammation (Held et al., 2015a). Very recently, a functional role of TRPM3 in the detection of noxious heat in mice was consolidated by demonstrating only the deletion of TRPM3, TRPV1 and TRPA1 produced a phenotype lacking the ability to detect acute noxious heat (Vandewauw et al., 2018). In a triple knock-out mouse lacking all three TRP channels, no robust heat responsiveness was observed on the cellular or behavioral level, while responsiveness to cold and mechanical stimuli as well as the preference for moderate temperatures was preserved (Vandewauw et al., 2018). This redundancy seems to constitute a fail-safe concept that ensures the avoidance of noxious heat even if one or two sensors are desensitized or malfunctioning and may exist for other harmful physical stimuli.

The endogenous mechanisms underlying TRPM3-dependent nociception have not yet been unraveled, but a short signaling cascade has been identified, which is initiated by the activation of Gαi/o-protein coupled receptors (GiPCRs) and leads to the inhibition of pro-nociceptive TRPM3 channels (Badheka et al., 2017; Dembla et al., 2017b; Quallo et al., 2017). This inhibition is mediated via G-protein βγ subunits that are released during GiPCR activation and form complexes with TRPM3 proteins leading to reduced TRPM3-dependent pain responses in vivo (Badheka et al., 2017; Dembla et al., 2017b; Quallo et al., 2017). TRPM3 seems to be under tonic GiPCR control, as application of GiPCR inverse agonists potentiated TRPM3-dependent nocifensive behavior (Quallo et al., 2017). However, when inverse agonists were applied systemically and the data were obtained during nociceptive in vivo tests, these agonists may have acted at several sites along the pain pathway. Activation of μ-opioid receptors, which belong to the group of GiPCRs, also inhibited TRPM3 strongly and rapidly (but not TRPV1 or TRPA1) in vitro and in vivo, indicating that this inhibition contributes to the peripheral analgesic effects of clinically used opioid drugs (Dembla et al., 2017b; Vriens and Voets, 2018).

Basic pharmacology – inhibitors

Several pharmacological TRPM3 antagonists have been identified and characterized recently, and some of them have already been tested for their analgesic efficacy on TRPM3-dependent pain.

Mefenamic acid is a rather potent and selective TRPM3 blocker with a half-maximal inhibitory concentration (IC50) of 6.6 μm (Klose et al., 2011). However, mefenamic acid can also activate TRPA1 with a half-maximal effective concentration (EC50) of 61 μm (Hu et al., 2010), which could be problematic studying cells co-expressing both channels like a subset of sensory neurons. The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone inhibits TRPM3 with an IC50 of 9.5 μm (nifedipine) or 4.6 μm (PregS), but it also inhibits TRPM2 [which was recently proposed to be required for warmth sensing (Tan and McNaughton, 2016)] with an IC50 of ~22.5 μm and it activates TRPC5 with an EC50 of ~30 μm (Majeed et al., 2011). Furthermore, the inhibitory effects of steroids were tested, and progesterone was found to suppress PregS-induced TRPM3 activity in the range of 0.01–10 μm as well as nifedipine-induced and basal TRPM3 activity (Majeed et al., 2012). Interestingly, while the L-type calcium channel blocker nifedipine activates TRPM3, the other dihydropyridines nicardipine, nimodipine and nitrendipine were found to inhibit (Drews et al., 2014), but all four listed dihydropyridines activate TRPA1 channels (Fajardo et al., 2008). In addition, the phospholipase C (PLC) inhibitor U73122, which has been used in many studies investigating the roles of PLC activity and PIP dynamics, was recently shown to inhibit TRPM3 (and activate the ubiquitously expressed TRPM4) (Leitner et al., 2016). Very recently, the TRPM3-calmodulin interaction proposed by Holakovska et al. (2012) was further corroborated (Przibilla et al., 2018) and therefore, the antagonistic effect of the calmodulin inhibitor W-7 on TRPM3 channels (IC50 of 15 μm) (Harteneck and Gollasch, 2011) might be worth mentioning.

The utilization of some of the described TRPM3 blockers in vitro has generated useful information about the channel’s properties and function. However, blockers with higher potency and selectivity are needed to perform in vivo studies and to test for usability in therapeutics and, luckily, several promising candidates have already been introduced.

The citrus fruit flavanones naringenin (IC50=0.5 μm) and hesperetin (IC50=2 μm) as well as the deoxybenzoin ononetin (IC50=0.3 μm) and eriodictyol (IC50=1 μm; a naringenin and hesperitin metabolite) were identified and characterized as blockers of TRPM3 activity in an overexpression system as well as in primary cultures of mouse or rat DRG neurons (Straub et al., 2013a). For naringenin, however, the list of known effects (and targets) is already relatively long, possibly limiting its therapeutic potential. For example, naringenin has been shown to inhibit two-pore channel 2 (Pafumi et al., 2017), to activate ATP-sensitive as well as Ca2+-activated K+ channels (Hsu et al., 2014; Meng et al., 2016; Testai et al., 2017) and to regulate CFTR activation and expression (Shi et al., 2017). Shortly afterwards, the flavanones isosakuranetin (IC50=50 nm) and liquiritigenin (IC50=0.5 μm) were presented, which both displayed a high selectivity for TRPM3 inhibition in DRG neurons (Straub et al., 2013b). After intraperitoneal injection of isosakuranetin or hesperetin, mice showed a reduced sensitivity to noxious heat as well as reduced pain responses after intraplantar PregS injection (Straub et al., 2013b). Interestingly, liquiritigenin was anti-nociceptive for heat, cold and mechanical hyperalgesia without impairing motor functions in a chronic constriction injury model of neuropathic pain in rats (Chen et al., 2014). However, liquiritigenin is not only a TRPM3 antagonist, but also inhibited the human aromatase enzyme CYP19 (Paoletta et al., 2008) and activated estrogen receptor β (Mersereau et al., 2008). In a similar study, isosakuranetin was tested for its anti-nociceptive effects in vivo and also alleviated heat, cold and mechanical hyperalgesia (Jia et al., 2017).

Apart from newly identified substances also approved drugs showed inhibitory effects towards TRPM3 channels, including the non-steroidal anti-inflammatory drug diclofenac [IC50=7.1–42.5 μm (Suzuki et al., 2016) and IC50=6.2 μm (Krügel et al., 2017)], the tetracyclic anti-depressant maprotiline (IC50=1.3 μm) and the anti-convulsant primidone (IC50=0.6 μm) (Krügel et al., 2017). Applying primidone at sub-therapeutic concentrations inhibited PregS- and PregS-clotrimazole responses in vitro and attenuated heat- and PregS-induced nocifensive behavior as well as inflammatory hyperalgesia in vivo (Krügel et al., 2017). The functions of TRPM3 channels expressed at afferent nerve fiber endings in the skin are summarized in Figure 1D. Although in vivo studies did not include controls utilizing TRPM3-deficient mice, their results and the tested compounds are promising and will help to further unravel the mechanisms of TRPM3-dependent pain and TRPM3’s potential as an analgesic target.

Outlook

Injection of the TRPM3 agonist PregS did not elicit hypothermia (Vriens et al., 2011) and systemic administration of TRPM3 antagonists did not result in alterations of the core body temperature in mice (Straub et al., 2013b), indicating that TRPM3 might be a more promising target for future analgesics than TRPV1. However, TRPM3 is widely expressed in other tissues and the expression patterns in rodents and humans are most likely not identical, why the exact expression patterns should be unraveled (Held et al., 2015b). Besides, TRPM3 expression in DRG satellite glia cells has also been described, opening a new direction for research in the field of TRPM3-dependent pain focusing on glia cells (Badheka et al., 2017; Dembla et al., 2017a). Moreover, nociception in mice and humans is also not identical (Rostock et al., 2018), why animal models that more closely reflect the human anatomical and physiological skin peculiarities like the pig (Obreja and Schmelz, 2010) should be included in studies investigating the role of TRPM3 in nociception and pain.

Taken together, TRPM3 is indeed a ‘hot’ candidate for a new and better target of future analgesics, but much basic research has to be performed in order to fully unravel its potential in pain therapy and to avoid the pitfalls experienced with TRPV1 modulators.

Acknowledgments

The author would like to thank PD Dr. Richard Carr for critically reading the manuscript.

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About the article

Received: 2018-12-07

Accepted: 2019-02-25

Published Online: 2019-03-23

Published in Print: 2019-06-26


Conflict of interest statement: The author declares no competing interests.


Citation Information: Biological Chemistry, Volume 400, Issue 7, Pages 917–926, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0455.

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