Author response: G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons

Quallo, Talisia; Alkhatib, Omar; Gentry, Clive; Andersson, David A.; Bevan, Stuart

doi:10.7554/elife.26138.013

Cited by 3 publications

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“…First, TRPM3 was shown to be abundantly expressed and functionally active in different brain regions (Oberwinkler and Philipp, 2014). Furthermore, TRPM3 can be modulated by several endogenous brain ligands and receptors (Held et al, 2015b;Badheka et al, 2017;Csanády, 2017;Dembla et al, 2017;Quallo et al, 2017). In addition, TRPM3 was also shown to be targeted by a commonly used anti-convulsion drug, primidone (Krügel et al, 2017), a compound of which the exact molecular actions are up until today still illusive.…”

Section: Discussionmentioning

confidence: 99%

“…In good accordance, signaling pathways decreasing endogenous PtdIns(4,5)P 2 , like phospholipase C activation evoked by M1 or M3 muscarinic acetylcholine receptors, inhibited both recombinant and native TRPM3 Tóth et al, 2015). G βγ subunits of trimeric G-proteins were also shown to be negatively coupled to TRPM3 activity, which underlies inhibition of TRPM3 upon stimulation of several Gprotein-coupled receptors, including G q -coupled M1 muscarinic acetylcholine, B2 bradykinin receptors and G i -coupled M2 muscarinic acetylcholine, D2 dopamine, GABA B , neuropeptide Y, µ-opioid receptors and G s -coupled EP-2 prostaglandin, and A2B adenosine receptors or receptors of somatostatin (Badheka et al, 2017;Dembla et al, 2017;Quallo et al, 2017;Alkhatib et al, 2019). A 10-amino-acid-long domain in TRPM3 was identified that interacted with G βγ proteins.…”

Section: Intrinsic Regulation By Signaling Moleculesmentioning

confidence: 99%

“…In addition, three recent studies reported in parallel on the modulation of TRPM3 by G βγ -proteins via a signaling cascade with GPCRs, such as GABA B -, µ-opioidand NPY receptors (Badheka et al, 2017;Dembla et al, 2017;Quallo et al, 2017). Of note, all of these receptors can be found abundantly in the brain (Hill and Bowery, 1981;Delfs et al, 1994;Reichmann and Holzer, 2016), and the inhibitory effects of endogenous, brain-relevant GPCR ligands such as somatostatin (Martel et al, 2012) and morphine (Beltrán-Campos et al, 2015) on TRPM3 currents were illustrated in these studies (Badheka et al, 2017;Dembla et al, 2017;Quallo et al, 2017). However, all of these studies were performed in heterologous expression systems or peripheral sensory neurons and no brain tissue was used to confirm similar actions.…”

Section: Function Of Trpm3 In the Brainmentioning

confidence: 99%

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TRPM3 in Brain (Patho)Physiology

Held

Tóth

2021

Front. Cell Dev. Biol.

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Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. This regulated ion permeation results in different electrical and chemical signals that are necessary to maintain physiological excitatory and inhibitory processes in the brain. Therefore, it is no surprise that disturbances in the functions of cerebral ion channels can result in a plethora of neurological disorders, which present a tremendous health care burden for our current society. The identification of ion channel-related brain disorders also fuel the research into the roles of ion channel proteins in various brain states. In the last decade, mounting evidence has been collected that indicates a pivotal role for transient receptor potential (TRP) ion channels in the development and various physiological functions of the central nervous system. For instance, TRP channels modulate neurite growth, synaptic plasticity and integration, and are required for neuronal survival. Moreover, TRP channels are involved in numerous neurological disorders. TRPM3 belongs to the melastatin subfamily of TRP channels and represents a non-selective cation channel that can be activated by several different stimuli, including the neurosteroid pregnenolone sulfate, osmotic pressures and heat. The channel is best known as a peripheral nociceptive ion channel that participates in heat sensation. However, recent research identifies TRPM3 as an emerging new player in the brain. In this review, we summarize the available data regarding the roles of TRPM3 in the brain, and correlate these data with the neuropathological processes in which this ion channel may be involved.

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Section: Discussionmentioning

confidence: 99%

Section: Intrinsic Regulation By Signaling Moleculesmentioning

confidence: 99%

Section: Function Of Trpm3 In the Brainmentioning

confidence: 99%

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TRPM3 in Brain (Patho)Physiology

Held

Tóth

2021

Front. Cell Dev. Biol.

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Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Madasu

Thang

Chilukuri

et al. 2020

Preprint

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Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.

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

Behrendt

2019

Biological Chemistry

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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.

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Author response: G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons

Cited by 3 publications

References 0 publications

TRPM3 in Brain (Patho)Physiology

TRPM3 in Brain (Patho)Physiology

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

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

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