TRPV Channels

TRPV channels are so called as a result of their activation by a group of compounds known as vanilloids, which includes capsaicin, compound found in chilli peppers. Capsaicin binds to TRPV1 channels and this binding is responsible for the hot, pain-like sensation caused by eating a spicy chilli.

Like all TRP channels, TRPV channels are cation selective ion channels formed from four individual subunits. They can exist as homo or heterotetramers and display extremely complex activation mechanisms. Different TRPV channels are activated by different stimuli, such as changes in temperature, mechanical stimuli, exogenous small molecules, and endogenous molecules and lipids, such as arachidonic acid metabolites, anandamide (Cat. No. 1339) and diacylglycerol (DAG). The response to a single stimulus cannot be mapped to a single TRPV channel as each channel responds to more than one stimulus. Also, TRPV channels can form heteromultimers, giving rise to channel complexes that can be activated by a wide range of stimuli.

TRPV Receptor Subtypes

Six TRPV channel subtypes have been identified, which can be grouped by their main function; TRPV1, TRPV2 and TRPV3 are thermosensors, TRPV4 is an osmosensor, and TRPV5 and TRPV6 are Ca²⁺ sensitive, Ca²⁺ selective channels. All TRPV channels are widely expressed. TRPV1 to 4 are expressed on afferent nociceptors where they act as transducers of thermal and chemical stimuli. Blockers of these receptors may have application in the prevention and treatment of various types of pain.

Table 1: TRPV Channel Subtype Function and Stimuli

TRPV1 is widely distributed in the peripheral and central nervous system. In the periphery TRPV1 functions as a noxious thermosensor (>43°C) and is heavily involved in detection and regulation of body temperature. TRPV1 is also activated by endogenous ligands such as anandamide (Cat. No. 1339) and NADA (Cat. No. 1568). Exogenous activators of TRPV1 include capsaicin (Cat. No. 0462), and allyl isothiocyanate found in mustard and wasabi. In the brain, TRPV1 is thought to mediate long-term depression (LTD) in the hippocampus, which is linked to a decrease in the ability to form new memories.

The sensitivity of TRPV1 to stimuli is not static; it is modulated by inflammatory mediators like bradykinin and prostaglandins. Phosphorylation of TRPV1 by protein kinase C (PKC) via phospholipase signaling pathways increases its sensitivity to noxious stimuli and may lead to hyperalgesia.

TRPV2 is most highly expressed in the lungs and spleen but is also found in the brain and in a subpopulation of large sensory neurons. This TRP channel functions as a noxious thermosensor (>52°C), although it has also been linked to many other cellular and physiological processes. In mice, TRPV2 is activated by cell stretching and hypo-osmolarity, suggesting it can also be an osmosensor, however the exact activation mechanism is yet to be discovered.

In cancer TRPV2 has a role in the negative regulation of apoptosis through the Fas/Fas ligand pathway. Overexpression of TRPV2, identified in some tumors, leads to abnormal signaling that drives unregulated cell proliferation and resistance to apoptotic stimuli. TRPV2 is also expressed on lymphocytes and myeloid cells in the immune system, where it mediates macrophage chemotaxis, cytokine releases, phagocytosis and inflammation.

In brain, TRPV2 is thought to be responsible for the anti-epileptic effects of cannabidiol (CBD; Cat. No. 1570). As well as being cannabinoid receptor agonists, plant-derived cannabinoids act as TRPV2 agonists. CBD binds to TRPV2 channels, resulting in a reduction in epileptic activity and decreased seizure incidence.

TRPV3 has wide expression but displays particularly high levels in keratinocytes in skin, where it senses warm temperatures. This ion channel is also thought to have a role in hair growth, as mutations in TRPV3 cause hair loss in mice.

TRPV4 is a thermosensor and osmosensor, which is activated by osmotic, thermal, chemical and mechanical stimuli. TRPV4 has roles in vascular function, skeleton growth and structural integrity, skin barrier function, lung and airway function, and in pain and nociception. In the brain, TRPV4 is responsible for regulating osmotic pressure. Like TRPV1, the sensitivity of TRPV4 to stimuli is modulated by inflammation and arachidonic acid metabolites. More than 50 pathogenic mutations have been described for TRPV4, associated with skeletal dysplasia, peripheral neuropathies, and neurological motor function disorders.

Both TRPV5 and TRPV6 are highly selective for Ca²⁺ over Na⁺ and are involved in reabsorption of Ca²⁺ across intestinal and kidney epithelia, and regulation of blood Ca²⁺ content. They show differing tissue expression profiles, with TRPV5 predominantly found in the distal convoluted tubule and connecting tubules of the kidney while TRPV6 displays a broader expression pattern, including the intestines, kidney, placenta, pancreas and sweat glands. Unlike the rest of the TRPV channel family, TRPV5 and TRPV6 are not thermosensitive, or activated by ligand binding; they are both constitutively open at physiological membrane potentials. They are also modulated by calmodulin binding in a Ca²⁺-dependent manner.

External sources of pharmacological information for TRPV Channels :

• IUPHAR Receptor Code

• BJP Guide

TRPV Gene Data

TRPV Pharmacological Data

References

Gunthorpe et al (2002) The diversity in the vanilloid (TRPV) receptor family of ion channels. TiPS 23 183. Clapham et al (2003) International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels; transient receptor potential channels. Pharmacol.Rev. 55 591. Alexander et al (2004) Guide to receptors and channels. Br.J.Pharmacol. 141 S89.