Editing Transient receptor potential channel (section)

== Clinical significance ==
Mutations in TRPs have been linked to [[neurodegeneration|neurodegenerative]] disorders, skeletal [[dysplasia]], kidney disorders,<ref name="pmid3129667"/> and may play an important role in cancer. TRPs may make important therapeutic targets.  There is significant clinical significance to TRPV1, TRPV2, TRPV3 and TRPM8’s role as thermoreceptors, and TRPV4 and TRPA1’s role as mechanoreceptors; reduction of chronic pain may be possible by targeting ion channels involved in thermal, chemical, and mechanical sensation to reduce their sensitivity to stimuli.<ref>
{{cite journal | vauthors = Levine JD, Alessandri-Haber N | title = TRP channels: targets for the relief of pain | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1772 | issue = 8 | pages = 989–1003 | date = August 2007 | pmid = 17321113 | doi = 10.1016/j.bbadis.2007.01.008 | doi-access = free }}</ref>  For instance the use of TRPV1 agonists would potentially inhibit [[nociception]] at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed.<ref name="pmid17616360">
{{cite journal | vauthors = Prevarskaya N, Zhang L, Barritt G | title = TRP channels in cancer | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1772 | issue = 8 | pages = 937–46 | date = August 2007 | pmid = 17616360 | doi = 10.1016/j.bbadis.2007.05.006 | doi-access = free }}</ref> The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain.<ref name="pmid3129667"/>   TRPV1 agonists inhibit nociception at TRPV1

=== Role in cancer ===
Altered expression of TRP proteins often leads to [[tumorigenesis]], as reported for TRPV1, TRPV6, TRPC1, TRPC6, TRPM4, TRPM5, and TRPM8.<ref name="pmid17616360"/> TRPV1 and TRPV2 have been implicated in breast cancer. TRPV1 expression in aggregates found at [[endoplasmic reticulum]] or [[Golgi apparatus]] and/or surrounding these structures in breast cancer patients confer worse survival.<ref>{{cite journal | vauthors = Lozano C, Córdova C, Marchant I, Zúñiga R, Ochova P, Ramírez-Barrantes R, González-Arriagada WA, Rodriguez B, Olivero P | display-authors = 6 | title = Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients | journal = Breast Cancer: Targets and Therapy| volume = 10 | pages = 161–168 | date = 15 October 2018 | pmid = 30410392 | pmc = 6197232 | doi = 10.2147/BCTT.S170208 | doi-access = free }}</ref>

TRPM family of ion channels are particularly associated with prostate cancer where TRPM2 (and its long noncoding RNA ''TRPM2-AS''), TRPM4, and TRPM8 are overexpressed in prostate cancer associated with more aggressive outcomes.<ref>{{cite journal | vauthors = Wong KK, Banham AH, Yaacob NS, Nur Husna SM | title = The oncogenic roles of TRPM ion channels in cancer | journal = Journal of Cellular Physiology | volume = 234 | issue = 9 | pages = 14556–14573 | date = February 2019 | pmid = 30710353 | doi = 10.1002/jcp.28168 | s2cid = 73432591 | url = https://ora.ox.ac.uk/objects/uuid:fabb30b0-db58-46b5-b4d6-8c7b82a36147 | url-access = subscription }}</ref> TRPM3 has been shown to promote growth and [[autophagy]] in clear cell renal cell carcinoma,<ref>{{cite journal | vauthors = Hall DP, Cost NG, Hegde S, Kellner E, Mikhaylova O, Stratton Y, Ehmer B, Abplanalp WA, Pandey R, Biesiada J, Harteneck C, Plas DR, Meller J, Czyzyk-Krzeska MF | display-authors = 6 | title = TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma | journal = Cancer Cell | volume = 26 | issue = 5 | pages = 738–53 | date = November 2014 | pmid = 25517751 | pmc = 4269832 | doi = 10.1016/j.ccell.2014.09.015 }}</ref> TRPM4 is overexpressed in [[diffuse large B-cell lymphoma]] associated with poorer survival,<ref>{{cite journal | vauthors = Loo SK, Ch'ng ES, Md Salleh MS, Banham AH, Pedersen LM, Møller MB, Green TM, Wong KK | display-authors = 6 | title = TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma | journal = Histopathology | volume = 71 | issue = 1 | pages = 98–111 | date = July 2017 | pmid = 28248435 | doi = 10.1111/his.13204 | s2cid = 4767956 | url = https://ora.ox.ac.uk/objects/uuid:5ea94e06-3bbd-4e08-b202-68e0757453f9 | url-access = subscription }}</ref> while TRPM5 has oncogenic properties in [[melanoma]].<ref>{{cite journal | vauthors = Palmer RK, Atwal K, Bakaj I, Carlucci-Derbyshire S, Buber MT, Cerne R, Cortés RY, Devantier HR, Jorgensen V, Pawlyk A, Lee SP, Sprous DG, Zhang Z, Bryant R | display-authors = 6 | title = Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel | journal = Assay and Drug Development Technologies | volume = 8 | issue = 6 | pages = 703–13 | date = December 2010 | pmid = 21158685 | doi = 10.1089/adt.2010.0334 }}</ref>

TRP channels take center stage in modulating [[chemotherapy]] resistance in breast cancer.<ref name=Chemo>{{cite journal |last1=Soussi |first1=M |last2=Hasselsweiller |first2=A |last3=Gkika |first3=D |title=TRP Channels: The Neglected Culprits in Breast Cancer Chemotherapy Resistance? |journal=Membranes |date=12 September 2023 |volume=13 |issue=9 |page=788 |doi=10.3390/membranes13090788 |doi-access=free |pmid=37755210 |pmc=10536409}} {{CC-notice|cc=by4}}</ref> Some TRP channels such as TRPA1 and TRPC5 are tightly associated with drug resistance during cancer treatment; TRPC5-mediated high Ca<sup>2+</sup> influx activates the transcription factor [[NFAT|NFATC3]] (Nuclear Factor of Activated T Cells, Cytoplasmic 3), which triggers [[p-glycoprotein]] (p-gp) transcription. The overexpression of p-gp is widely recognized as a major factor in [[Antineoplastic resistance|chemoresistance]] in cancer cells, as it functions as an active efflux pump that can remove various foreign substances, including chemotherapeutic agents, from within the cell.<ref name="Chemo" />
[[File:TRPC5 Chemo.jpg|upright=1.3|thumb|TRPC5-mediated chemoresistance:<ol type="a">
<li>TRPC5 overexpression activates the transcription factor NFATC3 Ca<sup>2+</sup> signaling pathway, leading to p-gp overexpression. Moreover, the overexpressed p-gp expels chemotherapeutic drugs such as [[doxorubicin]] triggering chemoresistance.</li>
<li>Chemoresistant breast cancer cells overexpressing TRPC5 transfer channel units to chemo sensitive recipient cells via [[extracellular vesicles]] (EV), leading to the development of TRPC5-mediated chemoresistance in these cells.<ref name="Chemo" /></li>
</ol>]]
Contrarily, other TRP channels, such as TRPV1 and TRPV2, have been demonstrated to potentiate the anti-tumorigenic effects of certain chemotherapeutic agents and TRPV2 is a potential biomarker and therapeutic target in triple negative breast cancer.<ref name="Chemo" />

=== Role in inflammatory responses ===
In addition to [[TLR4]] mediated pathways, certain members of the family of the transient receptor potential ion channels recognize [[Lipopolysaccharide|LPS]]. LPS-mediated activation of TRPA1 was shown in mice<ref>{{cite journal | vauthors = Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, Manenschijn JA, Fernández-Peña C, Talavera A, Kichko T, Navia B, Sánchez A, Señarís R, Reeh P, Pérez-García MT, López-López JR, Voets T, Belmonte C, Talavera K, Viana F | display-authors = 6 | title = TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins | journal = Nature Communications | volume = 5 | pages = 3125 | date = 20 January 2014 | pmid = 24445575 | pmc = 3905718 | doi = 10.1038/ncomms4125 | bibcode = 2014NatCo...5.3125M }}</ref> and ''Drosophila melanogaster'' flies.<ref>{{cite journal | vauthors = Soldano A, Alpizar YA, Boonen B, Franco L, López-Requena A, Liu G, Mora N, Yaksi E, Voets T, Vennekens R, Hassan BA, Talavera K | display-authors = 6 | title = Gustatory-mediated avoidance of bacterial lipopolysaccharides via TRPA1 activation in Drosophila | journal = eLife | volume = 5 | date = June 2016 | pmid = 27296646 | pmc = 4907694 | doi = 10.7554/eLife.13133 | doi-access = free }}</ref> At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8.<ref>{{cite journal | vauthors = Boonen B, Alpizar YA, Sanchez A, López-Requena A, Voets T, Talavera K | title = Differential effects of lipopolysaccharide on mouse sensory TRP channels | journal = Cell Calcium | volume = 73 | pages = 72–81 | date = July 2018 | pmid = 29689522 | doi = 10.1016/j.ceca.2018.04.004 | s2cid = 13681499 | url = https://lirias.kuleuven.be/handle/123456789/623401 | url-access = subscription }}</ref> LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.<ref>{{cite journal | vauthors = Alpizar YA, Boonen B, Sanchez A, Jung C, López-Requena A, Naert R, Steelant B, Luyts K, Plata C, De Vooght V, Vanoirbeek JA, Meseguer VM, Voets T, Alvarez JL, Hellings PW, Hoet PH, Nemery B, Valverde MA, Talavera K | display-authors = 6 | title = TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells | journal = Nature Communications | volume = 8 | issue = 1 | pages = 1059 | date = October 2017 | pmid = 29057902 | pmc = 5651912 | doi = 10.1038/s41467-017-01201-3 | bibcode = 2017NatCo...8.1059A }}</ref>