Inhibition of Canonical Transient Receptor Potential Channels 4/5 with Highly Selective and Potent Small-Molecule HC-070 Alleviates Mechanical Hypersensitivity in Rat Models of Visceral and Neuropathic Pain

Jalava, Niina; Kaskinoro, Janne; Chapman, Hugh; Morales, Miguel; Metsänkylä, Hanna; Heinonen, Sini; Koivisto, Ari

doi:10.3390/ijms24043350

Cited by 4 publications

(1 citation statement)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another TRPC4/5 antagonist HC-070 developed by Hydra and Boehringer Ingelheim is currently in clinical trial for the treatment of anxiety disorder and depression ( Wulff et al, 2019 ). HC-070 also had a significant anti-hypersensitivity effect in the established phase of the chronic constriction injury model ( Jalava et al, 2023 ). TRPC5 inhibitor GFB-887, currently in phase 2 clinical trial, is being developed by Goldfinch Bio for the treatment of kidney disease.…”

Section: Trpc4/5 Drug Discoverymentioning

confidence: 99%

Direct modulation of TRPC ion channels by Gα proteins

Kang,

Kim,

Park

et al. 2024

Front. Physiol.

View full text Add to dashboard Cite

GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP2 and releases DAG and IP3. This IP3 increases intracellular Ca2+ and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-Gi/o protein antibodies in GI smooth muscle, indicating the involvement of Gαi/o protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active GαiQL proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by Gi/o proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY58-60 amino acids at ARD of TRPC5 binds with Gi3 protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for Gi and Gq pathway as Gq pathway increases intracellular Ca2+ and the increased Ca2+ facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (IM) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-Gi protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.

show abstract

Section: Trpc4/5 Drug Discoverymentioning

confidence: 99%