Transient receptor potential cation channel subfamily M member 3 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''TRPM3''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

The product of this gene belongs to the family of

transient receptor potential Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TR ...

(TRP) channels. TRP channels are Ca²⁺ permeable non-selective cation channels that play roles in a wide variety of physiological processes, including

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts all ...

, heat and cold sensation, calcium and magnesium homeostasis. TRPMs mediates sodium and calcium entry, which induces

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

and a cytoplasmic Ca²⁺ signal. Alternatively spliced transcript variants encoding different isoforms have been -identified. TRPM3 was shown to be activated by the

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coin ...

pregnenolone sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activity Pre ...

as well as the synthetic compound CIM0216.

Peripheral heat sensation

TRPM3 is expressed in peripheral sensory neurons of the

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...

, and they are activated by high temperatures. Genetic deletion of TRPM3 in mice reduces sensitivity to noxious heat, as well as inflammatory thermal

hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...

. Inhibitors of TRPM3 were also shown to reduce noxious heat and inflammatory heat hyperalgesia, as well as reduce heat hyperalgesia and spontaneous pain in nerve injury induced neuropathic pain.

Receptor mediated inhibition

TRPM3 is robustly inhibited by the activation of cell surface receptors that couple to inhibitory heterotrimeric G-proteins (Gi) via direct binding of the

Gβγ Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structura ...

subunit of the G-protein to the channel. Gβγ was shown to bind to a short α-helical segment of the channel. Receptors that inhibit TRPM3 include

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin r ...

s and GABA_B receptors.

TRPM3 in the brain

Mutations in TRPM3 in humans, were recently shown to cause a intellectual disability and

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

. The disease associated mutations were shown to increase the sensitivity of the channel to agonists, and heat.

TRPM3 ligands, activators and modulators

Activators

*Heat *

Pregnenolone Sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activity Pre ...

CIM-0216 CIM-0216 is a chemical compound which acts as a potent and selective activator of the TRPM3 calcium channel. It produces nociception and inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body ti ...

Channel Blockers

Mefenamic acid Mefenamic acid is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain. Its name derives from its systematic name, dimethylphenylaminobenz ...

Citrus fruit ''Citrus'' is a genus of flowering trees and shrubs in the rue family, Rutaceae. Plants in the genus produce citrus fruits, including important crops such as oranges, lemons, grapefruits, pomelos, and limes. The genus ''Citrus'' is native to So ...

flavonoids Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

, e.g.

naringenin Naringenin is a flavorless, colorless flavanone, a type of flavonoid. It is the predominant flavanone in grapefruit, and is found in a variety of fruits and herbs. Structure Naringenin has the skeleton structure of a flavanone with three hyd ...

isosakuranetin Isosakuranetin, an O-methylated flavonoid, is the 4'-methoxy derivative of naringenin, a flavanone. Didymin, a disaccharide of isosakuranetin, occur e.g. in sweet orange, blood orange and mandarin. Isosakuranetin is a potent inhibitor of TRPM3 ch ...

and

hesperetin Hesperetin is the 4'-methoxy derivative of eriodictyol, a flavanone. Hesperetin's 7-O-glycoside, hesperidin, is a naturally occurring flavanon-glycoside, the main flavonoid in lemons and sweet oranges. Hesperetin (and naringenin, the parent flavan ...

, as well as

ononetin Ononetin is a natural product from the deoxybenzoin group, which is found in the Russian traditional medicine plant ''Ononis spinosa''. It acts as an inhibitor of the transient receptor potential ion channel TRPM3 and has analgesic effects in an ...

(a deoxybenzoin). #

Primidone Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures, as well as essential tremors. It is taken by mouth. Common side effects include sleepiness, poor coordination, nau ...

, a clinically used

antiepileptic Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

medication also directly inhibits TRPM3.

Activity Modulator

* pH

References

External links

* Ion channels {{membrane-protein-stub