**Background**
Transient Receptor Potential Canonical (TRPC) channels are a subfamily of non-selective cation channels that play critical roles in regulating intracellular calcium homeostasis. Among these, TRPC4 and TRPC5 are closely related channels expressed in various tissues, including the central nervous system and the kidneys, where they modulate signal transduction pathways. Dysregulation of these channels is implicated in various pathological conditions, including inflammatory responses and renal dysfunction. Given their specific roles in mediating calcium entry, the development of selective inhibitors is essential for understanding their physiological functions and exploring potential therapeutic interventions. In this context, we will introduce a potent and selective TRPC4/TRPC5 channel inhibitor – ML204.
**Definition**
ML204 is a potent, selective TRPC4/TRPC5 channel inhibitor with an IC50 value of 0.96 μM for TRPC4β-mediated intracellular calcium rise.
**In Vitro and In Vivo Studies**
According to the ML204 description, this compound exhibits high selectivity, being at least 19-fold more selective against TRPC6 and showing no appreciable effect on other TRP channels or voltage-gated sodium, potassium, or calcium channels. In terms of ML204 in vitro activity, the compound inhibits TRPC4β-mediated intracellular Ca2+ rise in HEK293 cells with an IC50 of 0.96 μM. It effectively blocks TRPC4β activity induced by Gi/o stimulation (via μ-opioid, 5HT 1A serotonin, and M2 muscarinic receptors) or Gq/11 stimulation (via endogenous M3-like muscarinic receptors). Additionally, QPatch clamp assays in HEK293 cells demonstrated an IC50 of 2.6 μM for the inhibition of DAMGO-induced current. ML204 also blocks LPS-induced TRPC5 channel activity.
Regarding ML204 In Vivo studies, the compound was administered to nonfasted male C57BL/6 mice (2-3 months old) at a dosage of 1 mg/kg via subcutaneous injection twice a day for 5 days prior to LPS injection. The results indicated that ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS-injected mice. For researchers seeking detailed ML204 technical information, these findings highlight the compound’s significant impact on the systemic inflammatory response. In conclusion, ML204 is a potent and selective inhibitor of TRPC4 and TRPC5 channels suitable for pharmacological research.
Keywords
ML204, 5465-86-1, ML 204, ML-204, TRP Channel, Transient receptor potential channels, ion, channels, membrane, biophysics, transport, receptor, regulation, transient, potential, canonical, TRP, Inhibitor, inhibitor, inhibit
References
[1] Miller M, et al. Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem. 2011 Sep 23;286(38):33436-46.
[2] Miller MR, et al. Novel Chemical Inhibitor of TRPC4 Channels. Probe Reports from the NIH Molecular Libraries Program [Internet].
[3] Thomas Schaldecker, et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013 Dec 2; 123(12): 5298–5309.
[4] Domingos M S Pereira, et al. Transient Receptor Potential Canonical Channels 4 and 5 Mediate Escherichia coli-Derived Thioredoxin Effects in Lipopolysaccharide-Injected Mice. Oxid Med Cell Longev. 2018 Jun 10;2018:4904696.