Mammalian transient receptor potential (TRP) channels encompass over 25 members, and exert wide-ranging functions peripherally and centrally. These non-selective cation channels form a major class of Ca2+-permeable channels, and are classified into six further subfamilies, based on amino acid sequence homology. TRPC5 is a member of the canonical subfamily which comprise six members in humans. TRPC5 is widely expressed in the central nervous system and, to a lesser extent, in the periphery. So far, there is only one drug that has demonstrated efficacy for severe cold-induced pain associated with diabetic and chemotherapy-induced neuropathy. It is unknown why this drug – duloxetine, Cymbalta a medication sold under the brand name, is more effective than other serotonin and norepinephrine reuptake inhibitors at treating these conditions. Duloxetine’s clinical effectiveness is probably a result of both its central and peripheral activities. Duloxetine enhances the synaptic concentration of analgesic neurotransmitters in the brain, similar to other serotonin and norepinephrine reuptake inhibitors. This somewhat mimics the natural method by which the body attenuates pain and encourages survival in a stressful scenario. Duloxetine is hypothesized to inhibit the activity of nociceptive sensory neurons in the periphery by effectively inhibiting the voltage-gated sodium channels that regulate action potential propagation. TRPM8, TRPA1, and TRPC5 are currently thought to play a role in how humans perceive cold. Through an open channel block mechanism, duloxetine prevents TRPM8 from functioning. It has only recently been shown that 75% of human sensory neurons express TRPC5, and that genetic or pharmacological suppression of TRPC5 reduces chronic pain in a variety of rodent models, including neuropathic cold pain. Prior to the recent confirmation of a role for TRPC5 in cold-induced pain in teeth, in vivo relevance for the cold sensitivity associated with TRPC5 in a heterologous expression system was absent.
In a recent study that was published in the journal Biomedicine & Pharmacotherapy Researchers at the Institute of Physiology of the Czech Academy of Sciences: Dr. Lucie Zimova, Alexandra Ptakova, Michal Mitro, Dr. Jan Krusek and Dr. Viktorie Vlachova hypothesized that TRPC5 receptor is altered by duloxetine and may play a role in its analgesic action. The authors demonstrate that duloxetine directly inhibits the human TRPC5 ion channel, which is expressed in non-excitable cells as well as neuron-like F11 cells originating from sensory dorsal root ganglion neurons, at clinically relevant concentrations.
The research team demonstrated that duloxetine is a strong TRPC5 channel inhibitor, and its inhibitory action is state-dependent, which they showed by electrophysiology and calcium imaging. Researchers demonstrated that duloxetine substantially depends on voltage to suppress agonist-induced TRPC5 currents. Their in silico studies indicated that the voltage sensor-like domain’s (VSLD) interior cavity contains the duloxetine-TRPC5 interaction site. This notion was supported by mutagenesis, which revealed that neutralizing just one glutamate (E418) was sufficient to stop duloxetine from having an inhibitory effect upon voltage activation probably due to the disruption of the putative hydrogen bond. Furthermore, all known duloxetine-sensitive TRP family members share several conserved putatively interacting VSLD residues. The TRPC1 shares only two of these residues and in line with this duloxetine decreases the activity of heteromeric TRPC1/TRPC5 channels only partially. Together, these results lend credence to the notion that duloxetine binds to the VSLD pocket. There is no denying the complexity and involvement of numerous molecular targets in the course of duloxetine’s analgesic effect. Here, they demonstrate that TRPC5 should be counted among them. These findings imply that TRPC5 might be a previously unknown target for a widely prescribed, highly effective medication against really severe kinds of pain.
In conclusion, Dr. Lucie Zimova and colleagues elucidated detailed mechanism of how duloxetine blocks a variety of TRPC5 activation mechanisms, including currents induced by cooling or by the stimulation of the PLC pathway. According to the authors, duloxetine binds to the VSLD cavity that is known to house regulatory chemicals in TRPs. The potency of duloxetine’s impact on TRPC5 is within the physiological range and may help explain why duloxetine has both a peripheral and a central analgesic effect.
Zimova L, Ptakova A, Mitro M, Krusek J, Vlachova V. Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain. Biomedicine & Pharmacotherapy. 2022 Aug 1;152:113262.