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The Nociceptive TRPM3 Channel As Potential Therapeutic Target for the Treatment of Chronic Pain August 2017

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The Nociceptive TRPM3 Channel As Potential Therapeutic Target for the Treatment of Chronic Pain August 2017 Internal Medicine Review The nociceptive TRPM3 channel as potential therapeutic target for the treatment of chronic pain August 2017 Authors ABSTRACT Katharina Held1,2 Chronic pain is a major health problem affecting millions of Thomas Voets2 people worldwide. Despite decades of research, chronic pain Joris Vriens1 remains poorly understood and notoriously hard to control. Indeed, about half of the chronic pain sufferers report Affiliations: inadequate pain control with current analgetics. Therefore, 1 Laboratory of identification of novel potential drug targets as a starting Experimental Gynecology point in the development of novel painkillers represents an and G-PURE, KU Leuven, important aim in pain research. Several members of the Herestraat 49 box 611, B- Transient Receptor Potential (TRP) ion channel superfamily 3000 Leuven, Belgium are highly expressed in sensory neurons, where they play a 2 Laboratory of Ion Channel role in the detection of painful stimuli. Here, we will provide Research and TRP Research a detailed overview of a recently identified nociceptive TRP Platform Leuven (TRPLe), channel, TRPM3, as a promising target for the treatment of KU Leuven, Herestraat 49 chronic pain. box 802, B-3000 Leuven, Belgium Key words: TRP channels, TRPM3, pain, sensory neurons Corresponding author: Joris Vriens Herestraat 49, box 611 3000 Leuven Belgium [email protected] The authors declare no conflict of interest. 1 Copyright 2017 Internal Medicine Review. All Rights Reserved. Volume 3, Issue 8. Internal Medicine Review The nociceptive TRPM3 channel as potential therapeutic target for the treatment of chronic pain August 2017 GENERAL INTRODUCTION: second-order neurons located in the dorsal Pain – Ion channels horn (2, 3). The neurons are functionally Chronic pain management represents a characterized by the type of sensory ion serious healthcare problem worldwide, as it channels expressed on the plasma affects approximately 14.6% of the adult membrane. These ‘sensory’ ion channels are population within the United States (1). important for the detection of various Unfortunately, its management in the noxious stimuli including thermal (e.g. heat community remains generally or cold), mechanical (e.g. crushing or unsatisfactory, as currently available shearing) and chemical signals (e.g. acid or analgesics often show insufficient pain chemicals released during inflammation). relief. Classical medicines used to relieve These ion channels, expressed at the plasma pain, including nonsteroidal anti- membrane of sensory nerve endings, convert inflammatory drugs (NSAIDs) and opioids, the noxious stimuli into electrical signals, are among the most used drugs. However, which then travel from the periphery to the long-term treatment with these analgesics CNS in the form of action potentials (2, 3). for chronic pain is hampered by inter- In recent years, various types of ion individual variability in drug efficacy, channels, including members of the unwanted side-effects. Accordingly, for a Transient Receptor Potential (TRP) better control of chronic pain a deeper channels, have been identified as highly knowledge of the underlying molecular sensitive molecular pain detectors or mechanisms is mandatory. ‘nociceptor’ channels. These discoveries Nociceptive pain serves as a protective have fueled detailed studies examining the mechanism and an associative condition, as molecular and cellular mechanisms of well as an alarm system for a wide range of nociception and have led to the development pathological conditions. The first and of novel targets for the treatment of pain (4). foremost process is the peripheral detection Here, we provide a brief overview of the and transduction of noxious stimuli, which role of a recently characterized member of are conveyed to higher-order structures in the TRP superfamily in sensory neurons, the central nervous system (CNS). TRPM3, as nociceptive channel, and of its Typically, nociceptive neurons are either therapeutic potential as a target for the thinly myelinated A or unmyelinated small treatment of chronic pain. In addition, we diameter - low conduction velocity C fibers. discuss properties of TRPM3 in comparison The cell bodies of these neurons are located to previously defined therapeutic targets like in the dorsal root ganglia (DRG) or TRPV1. trigeminal ganglia (TG), and they have one axon with two branches, with one branch Nociceptive TRP channels extending to the peripheral tissues such as The superfamily of TRP channels contains skin and internal organs, and the other 28 mammalian members (27 in humans) and branch relaying the detected information to is subdivided based on sequence homology 2 Copyright 2017 Internal Medicine Review. All Rights Reserved. Volume 3, Issue 8. Internal Medicine Review The nociceptive TRPM3 channel as potential therapeutic target for the treatment of chronic pain August 2017 into six subfamilies, categorized as expression of nociceptive TRP channels are Canonical (TRPC), Vanilloid (TRPV), critically implicated in the development of Ankyrin (TRPA), Melastatin (TRPM), hypersensitivity and pain under a variety of Polycystin (TRPP), and MucoLipin pathological conditions. These findings (TRPML) (5). Typically, TRP channels indicate that pharmacological targeting of contain six transmembrane spanning regions TRP channels may be a novel means to treat (S5-S6), a pore-forming loop between the specific pain pathologies. fifth (S5) and sixth (S6) regions and During the past decennia, several intracellular N- and C- termini (Fig. 1A) (6). nociceptive TRP channels have been Assembly of four of these subunits into identified, including TRPV1, TRPM8 and homo- or heteromultimers results in TRPA1 (10). The first molecularly identified functional ion channels (Fig. 1B) (7). TRP nociceptor TRP channel was TRPV1, which channels are mostly non-selective cation was discovered based on its sensitivity to channels with, except for TRPM4 and capsaicin, the pungent compound of hot chili TRPM5, significant calcium permeability. peppers (11). Like the majority of TRP They are found in a wide variety of cell channels, TRPV1 is polymodal in terms of types, both on the plasma membrane and in its activation. Indeed, in addition to intracellular organelle membranes (8). capsaicin, the channel can be directly Several TRP channels act as primary activated by endovanilloids such as N- transducers of sensory stimuli, making the arachidonoyl-dopamine and TRP superfamily one of the most endocannabinoids such as anandamide (12- extensively studied receptor families in 14), as well as by heat, extracellular acidity, sensory biology (9). (~ ≤ pH 6.0) (11, 15, 16), and intracellular Based on their ability to detect and transduce alkalinisation (~ ≥ pH 7.8) (17). Importantly, specific nociceptive modalities and their Trpv1 knockout mice not only lack expression in sensory neurons, some sensitivity to capsaicin, but also fail to members of the TRP superfamily have been develop thermal hyperalgesia after grouped into the category of ‘nociceptive inflammation and injury (18-20). TRP channels’. Activation of nociceptive TRPM8 was identified as the first TRP TRP channels by specific pain-producing channel involved in cold detection by the stimuli generates cell depolarization, which somatosensory system (21, 22). Trpm8- can result in activation of voltage-gated ion deficient mice exhibit a deficit in avoiding channels and generation of action potentials cool temperatures (23, 24). Moreover, (Fig. 1C). Therefore, these channels serve as whereas mild cooling can evoke analgesia in the primary molecular sensors for the wild-type mice, cooling induced analgesia detection and transduction of pain under was absent in Trpm8-deficient mice (24). physiological and pathophysiological TRPA1 was originally described as a cold conditions (10). In addition, modifications in sensitive ion channel (25-28), although this channel function, trafficking or gene conclusion has been debated by others (29). 3 Copyright 2017 Internal Medicine Review. All Rights Reserved. Volume 3, Issue 8. Internal Medicine Review The nociceptive TRPM3 channel as potential therapeutic target for the treatment of chronic pain August 2017 TRPA1 can be activated by a plethora of somatosensory neurons, where TRPM3 is chemically diverse noxious or irritant involved in the sensation of painful stimuli compounds (27, 30, 31). Several in vivo (40, 43, 44). studies have shown that Trpa1-deficient mice have marked deficiencies in the Biophysical characteristics nocifensive responses to such chemical The biophysical characteristics of TRPM3 agents as well as to noxious cold (25, 32, channels have been extensively investigated 33). in heterologous overexpression systems. The role of TRPV1, TRPM8 and TRPA1 in Typically, heterologous overexpression of pain has been extensively reviewed TRPM3 proteins results in a small but elsewhere (10). Below we provide a current significant constitutive conductance (35, 36, view of (patho) physiological roles of the 45), which can be further increased by more recently identified nociceptor channel various ligands (see below). Similar TRPM3. properties have been described for endogenously expressed TRPM3 channels in TRPM3 pancreatic cells and primary cultures of The human Trpm3 gene is the largest gene mouse DRG and TG (38, 40). Reported on chromosome 9 (9q21.11-q21.12 (34), and single channel conductances are ~65 pS in TRPM3 was originally described as a the presence of Ca2+ and ~83 pS when solely volume-regulated, non-selective,
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