CIM0216 is a Potent and Selective Agonist of TRPM3

Transient receptor potential (TRP) channels are large and nonselective cation channels. It can respond to a wide range of chemical and physical stimuli and biophysical properties. TRPM3 acts as a permeable nonselective cation channel. And it acts as a typical example of a polymodally gated TRP channel. TRPM3 is highly expressed in somatosensory neurons. They play an important role in the nocifensive response to PS and heat. Besides, it also plays a critical role in the development of heat hyperalgesia during inflammation.
TRPM3 often coexpresses with TRPA1 and TRPV1. The two TRP channels emerge as key regulators of neurogenic inflammation by triggering neuropeptide release from sensory nerve endings. However, it is not clear that TRPM3 can initiate the release of neuropeptides, such as substance P or calcitonin gene-related peptide (CGRP), et al. These neuropeptides can elicit vasodilation, vascular leakage, and other responses in peripheral cell types.

Additionally, TRPM3 also expresses in pancreatic beta cells and involves in controlling insulin release. The physiological roles of TRPM3 in these tissues are poorly understood. And it is necessary to find potent and specific pharmacologic tools for TRPM3 research.

In this article, we will introduce a potent and selective agonist of TRPM3, CIM0216.

CIM0216 has the ability to open two distinct cation-permeable pores in TRPM3. Besides, it exhibits selectivity for TRPM3 over TRPM1, TRPM2, and TRPM4-8. CIM0216 elicits a dose-dependent Ca2+ response [pEC50=0.77±0.1 µM] in HEK-TRPM3 cells. But the response is not observed in nontransfected HEK293 cells.

In a single-cell FURA2-ratiometric Ca2+ imaging in HEK-TRPM3 cells, CIM0216 induces a robust increase in intracellular Ca2+ concentration (1,145±26 nM). Furthermore, CIM0216 (10 µM) has no stimulating/blocking effect on TRPM1, TRPM4, TRPM6, or TRPM7 currents. However, a small blocking effect of CIM0216 is observed after activation of TRPM2 (16.6% block) and TRPM5 (33.5% block). CIM0216 also has no detectable effect on human TRPV1 and TRPM8 channel activation.

In conclusion, CIM0216 acts as a powerful tool for use in investigating the physiological roles of TRPM3.


[1]. Katharina Held, et al. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1363-72.