Transient receptor potential (TRP) channels: a clinical perspective

Abstract

Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field. LINKED ARTICLESThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx

The role of transient receptor potential channels in joint diseases

“…Most conclusive data are available on the pathomechanisms of hereditary TRP-linked diseases (Nilius and Owsianik, 2010). The current understanding of acquired TRP channel disorders is limited, as it is mainly based on in vitro studies or rodent models, which do not always well represent human diseases (Kaneko and Szallasi, 2014).…”

Genetic variants affecting human TRPA1 or TRPM8 structure can be classified in vitro as ‘well expressed’, ‘poorly expressed’ or ‘salvageable’

“…The cold-temperature-sensitive TRPA1 (transient receptor potential A1) and TRPM8 (transient receptor potential M8) Na + , Ca 2 + ion channels are interesting pharmacological targets due to their roles in sensory nerve activation, pain and inflammation [1,2]. These channels are formed as homo-tetrameric complexes, with each subunit containing approximately 1100 amino acid residues.…”

Cannabinoids, the Heart of the Matter

“…TRPV1 ion channels have important functions as cellular sensors, and are involved in nociception, taste perception, thermosensation, mechano‐ and osmolarity sensing, and regulation of signal transmission 15, 55, 56. In addition to ECS and physicochemical activators,15, 33, 55, 56, 57, 58 TRPV1 is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs of THC and cannabigerol 59, 60, 61, 62, 63, 64, 65, 66, 67. Cannabichromene (CBC), cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV (from a botanical extract) is a potent regulator of TRPA1 62…”

“…TRPV1 channel ligation can be beneficial in one organ and induce unacceptable adverse side effects in another 56. For example, in clinical trials, small molecule TRPV1 (TRPV3 and TRPA1) antagonists were used to treat inflammatory, neuropathic, and visceral pain, but studies were terminated because of adverse effects induced by TRPV1 antagonists 100.…”