Current Pharmaceutical Biotechnology - Volume 12, Issue 1, 2011

It is my pleasure to introduce this “Hot Topic” special issue of Current Pharmaceutical Biotechnology, focusing on the family of cation channels that have attracted considerable attention and research work during the past decade as a target class for drug discovery. These channels are called the ‘transient receptor potential’ (TRP) ion channels because deletion of the trp gene, initially discovered in a fruit fly, caused the photoreceptor potential in response to steady light to switch from sustained into transient. Mammalian TRP channels are encoded by 28 genes and can be classified into six main subfamilies: canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), ankyrin (TRPA), polycystin (TRPP), and mucolipin (TRPML) (for nomenclature, please see [1], and references therein). Along with classical ligand-binding mechanisms, TRP channels are able to detect and transduce environmental inputs, such as temperature, light, osmotic pressure, cell membrane deformation or depolarization. These unique activation properties make them ideal candidates for being directly involved in sensory modalities: vision, temperature reception, olfaction, osmosensation, hearing, voltage, taste and nociception. Indeed, the cloning of temperature sensitive members of the TRPV, TRPA or TRPM channel subfamilies from mammalian sensory ganglion cDNA libraries has provided clues to the proteins that detect and evaluate particularly those stimulus modalities that may damage or threaten to damage tissue. In this special issue, we hope to offer readers an informative yet concise insight into the exciting field of research on TRP channels, highlighted from different experts. Their reviews detail current insights into the inner workings of these remarkable channels and deal with recent advances and hurdles that must be overcome when considering TRP channel agonists, antagonists or modulators for future therapeutic evaluation. The modalities of activation of TRP channels are diverse, but they do have something in common: their transmembrane domains have similar architecture, determined by similar physical principles, in particular in terms of the permeability and selectivity of cations, gating the pore and sensing voltage. Víctor M. Meseguer, Bristol L. Denlinger and Karel Talavera focus their review on a number of methodological considerations that are essential to be taken into account when studying the role of TRP channels as sensors and integrators of chemical stimuli. Accumulated evidence suggests that, in addition to the TRP channels localized on the plasma membrane, intracellularly localized TRP channels also actively participate in regulating membrane traffic, vesicular ion homeostasis and signal transduction. The features of the TRP-residing compartments and the processes related to TRP channel trafficking and their insertion into the plasma membrane are highlighted by the article of Carlos A. Toro, Luis A. Arias and Sebastian Brauchi. Primary afferent neurons supplying the gastrointestinal tract can be sensitized in response to pro-inflammatory mediators, and so the mechanisms whereby hypersensitivity is initiated and maintained are of prime therapeutic interest. Although TRP channels contribute to sensory transduction in every region of the body, they play a particular role in the alimentary canal. This special position derives from their function as molecular sensors for distinct chemical and physical modalities that are rather specific to the digestive system. The role of TRP channels in these processes is reviewed by Peter Holzer. The canonical TRPC channels (TRPC1-7) share the common property of activation through phospholipase C-coupled receptors. Christian Harteneck and Maik Gollasch focus on the mechanisms of pharmacological modulation in the specific subclass of TRPC channels, TRPC3/6/7, which are also gated by direct exposure to diacylglycerols. The authors discuss a broad number of drugs that interfere with TRPC3/6/7 activity and function.....

Transient Receptor Potential channels are exquisite molecular transducers of multiple physical and chemical stimuli, hence the raising interest to study their relevance to Sensory Biology. Here we discuss a number of aspects of the biophysical and pharmacological properties of TRP channels, which we consider essential for a clear understanding of their sensory function in vivo. By examining concrete examples extracted from recent literature we illustrate that TRP channel research is a field in motion, and that many established dogmas on biophysical properties, drug specificity and physiological role are continuously reshaped, and sometimes even dismantled.

Cellular electrical activity is the result of a highly complex process that involve the activation of ion channel proteins. Ion channels make pores on cell membranes that rapidly transit between conductive and non-conductive states, allowing different ions to flow down their electrochemical gradients across cell membranes. In the case of neuronal cells, ion channel activity orchestrates action potentials traveling through axons, enabling electrical communication between cells in distant parts of the body. Somatic sensation -our ability to feel touch, temperature and noxious stimuli- require ion channels able to sense and respond to our peripheral environment. Sensory integration involves the summing of various environmental cues and their conversion into electrical signals. Members of the Transient Receptor Potential (TRP) family of ion channels have emerged as important mediators of both, cellular sensing and sensory integration. The regulation of the spatial and temporal distribution of membrane receptors is recognized as an important mechanism for controlling the magnitude of the cellular response and the time scale on which cellular signaling occurs. Several studies have shown that this mechanism is also used by TRP channels to modulate cellular response and ultimately fulfill their physiological function as sensors. However, the inner-working of this mode of control for TRP channels remains poorly understood. The question of whether TRPs intrinsically regulate their own vesicular trafficking or weather the dynamic regulation of TRP channel residence on the cell surface is caused by extrinsic changes in the rates of vesicle insertion or retrieval remain open. This review will examine the evidence that sub-cellular redistribution of TRP channels plays an important role in regulating their activity and explore the mechanisms that control the trafficking of vesicles containing TRP channels.

Several of the 28 mammalian transient receptor potential (TRP) channel subunits are expressed throughout the alimentary canal where they play important roles in taste, chemo- and mechanosensation, thermoregulation, pain and hyperalgesia, mucosal function and homeostasis, control of motility by neurons, interstitial cells of Cajal and muscle cells, and vascular function. While the implications of some TRP channels, notably TRPA1, TRPC4, TRPM5, TRPM6, TRPM7, TRPV1, TRPV4, and TRPV6, have been investigated in much detail, the understanding of other TRP channels in their relevance to digestive function lags behind. The polymodal chemo- and mechanosensory function of TRPA1, TRPM5, TRPV1 and TRPV4 is particularly relevant to the alimentary canal whose digestive and absorptive function depends on the surveillance and integration of many chemical and physical stimuli. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 appear to be essential for the absorption of Ca2+ and Mg2+, respectively, while TRPM7 appears to contribute to the pacemaker activity of the interstitial cells of Cajal, and TRPC4 transduces smooth muscle contraction evoked by muscarinic acetylcholine receptor activation. The implication of some TRP channels in pathological processes has raised enormous interest in exploiting them as a therapeutic target. This is particularly true for TRPV1, TRPV4 and TRPA1, which may be targeted for the treatment of several conditions of chronic abdominal pain. Consequently, blockers of these TRP channels have been developed, and their clinical usefulness has yet to be established.

Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A2 inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, selective and more potent modulators of TRPC3/6/7 activity.

Unique among ion channels, TRPM6 and TRPM7 garnered much interest upon their discovery as the first ion channels to possess their own kinase domain. Soon after their identification, the two proteins were quickly linked to the regulation of magnesium homeostasis. However, study of their physiological functions in mouse and zebrafish have revealed expanding roles for these channel-kinases that include skeletogenesis and melanopore formation, thymopoiesis, cell adhesion, and neural fold closure during early development. In addition, mutations in the TRPM6 gene constitute the underlying genetic defect in hypomagnesemia with secondary hypocalcemia, a rare autosomal-recessive disease characterized by low serum magnesium accompanied by hypocalcemia. Depletion of TRPM7 expression in brain, on the other hand, proved successful in mitigating much of the cellular devastation that accompanies oxygen-glucose deprivation during ischemia. The aim of this review is to summarize the data emerging from molecular genetic, biochemical, electrophysiological, and pharmacological studies of these unique channel-kinases.

Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by cold temperature and cooling agents. TRPM8 is expressed in a subpopulation of cold-sensitive sensory neurons, as well as in the male urogenital system. TRPM8 is markedly upregulated in prostate cancer and in other tumors such as breast adenocarcinoma and melanoma. Moreover, recent studies suggest the potential involvement of TRPM8 channels in the pathophysiology of cold nociception and cold allodynia. This has led to a strong interest in the pursuit of novel modulators of TRPM8 channels. This review highlights our current knowledge of TRPM8 pharmacology and modulation mechanisms, detailing structural features important for TRPM8 gating by different agonists, the mechanism of antagonism by different compounds and the potential relevance of TRPM8 for treatment of various pathological conditions.

Temperature perception is vital for cellular and metabolic homeostasis, avoidance, and survival. In the primary afferent nerve terminal, select members of the transient receptor potential (TRP) family of ion channels reside and convert thermal stimuli into neuronal activity. The cold and menthol receptor, TRPM8, is the predominant thermoceptor for cellular and behavioral responses to cold temperatures. Remarkably, this single molecular sensor of cold, that responds at a discrete thermal threshold in vitro (∼28°C), enables sensory afferents to respond to distinct, yet varied thermal thresholds (∼28 to <5°C). Thus, unlike other thermally-gated TRP channels which are activated at either innocuous or noxious temperatures, TRPM8 provides perception of both pleasantly cool and painfully cold. In addition to this diversity in sensory signaling, TRPM8 has an emerging role in a variety of biological systems, including thermoregulation, cancer, bladder function, and asthma. Here we summarize some key points related to TRPM8 and its potential as a drug target to treat a wide variety of physiological conditions. Nonetheless, it remains to be seen how this single “cool” molecule can serve in such a multitude of biological processes.

Temperature sensing is a crucial feature of the nervous system, enabling organisms to avoid physical danger and choose optimal environments for survival. TRPM8 (Transient Receptor Potential Melastatin type 8) belongs to a select group of ion channels which are gated by changes in temperature, are expressed in sensory nerves and/or skin cells and may be involved in temperature sensing. This channel is activated by a moderate decrease in temperature, with a threshold of ∼25 °C in heterologous expression systems, and by a variety of natural and synthetic compounds, including menthol. While the physiological role of TRPM8 as a transducer of gentle cooling is widely accepted, its involvement in acute noxious cold sensing in healthy tissues is still under debate. Although accumulating evidence indicates that TRPM8 is involved in neuropathic cold allodynia, in some animal models of nerve injury peripheral and central activation of TRPM8 is followed by analgesia. A variety of inflammatory mediators, including bradykinin and prostaglandin E2, modulate TRPM8 by inhibiting the channel and shifting its activation threshold to colder temperatures, most likely counteracting the analgesic action of TRPM8. While important progress has been made in unraveling the biophysical features of TRPM8, including the revelation of its voltage dependence, the precise mechanism involved in temperature sensing by this channel is still not completely understood. This article will review the current status of knowledge regarding the (patho)physiological role(s) of TRPM8, its modulation by inflammatory mediators, the signaling pathways involved in this regulation, and the biophysical properties of the channel.

TRPV1 and TRPA1 have traditionally been considered to function independently from each other as homomers, but their extensive co-expression in sensory neurons and recent evidence suggest that these channels can functionally interact and may form a complex as part of their normal function. Although TRPA1 and TRPV1 do not absolutely require interaction to maintain function in expression systems or even sensory neurons, their heteromerization may still result in dramatic effects on channel biophysical properties, pharmacology, signaling, regulation, and ultimately function. Understanding the regulation and functional significance of TRPA1-TRPV1 interaction is of tremendous clinical importance since first, both channels are the potential molecular targets for numerous therapeutic drugs; and second, TRPA1- TRPV1 co-expression is far more specific for nociceptive sensory neurons than expression patterns of TRPA1 or TRPV1 considered separately.

Transient Receptor Potential Vanilloid Type 1 is a prominent “pain” receptor expressed in sensory afferent neurons. TRPV1 on peripheral nerve terminals detects a variety of noxious stimuli generated at sites of injury and inflammation, and in turn, drives the excitation and sensitization of C-fiber neurons. Significantly, TRPV1 is also located on the central terminals of sensory neurons projecting to the spinal cord and brainstem. These TRPV1 channels appear to stimulate the secretion of glutamate. Further, TRPV1 is expressed diffusely in the brain and there is emerging evidence for TRPV1 modulating transmission at various brain synapses. Here we discuss our current understanding of the potential roles for TRPV1 in synaptic transmission.

The cloning of the first sensory Transient Receptor Potential (TRP) channel, TRPVanilloid 1 (TRPV1) in 1997, initiated a new era of pain research and coincided with the Decade of Pain Control and Research promulgated by the United States Congress. When cloned, TRPV1 channel was shown to be predominantly expressed in nociceptors (C- and A -fibers) and are activated by physical and chemical stimuli. Channel function can be amplified by transcriptional upregulation and posttranslational modification by proinflammatory agents. Indeed, TRPV1 gene disruption confirms that it is involved in transmitting inflammatory thermal hypersensitivity, but not acute thermal or mechanical pain sensitivity. Based on its distribution and functions, TRPV1 is considered as an ideal target for developing small molecule antagonists. Now, there is a growing body of evidence that TRPV1 is expressed in non-sensory neurons and non-neuronal cells. This raises the possibility of unwanted effects that may result from targeting TRPV1. A major consequence of TRPV1 blockade that has come to light in clinical trials following administration of antagonists is hyperthermia. This observation has threatened the abandonment of TRPV1 antagonists, although they are proven to be useful in certain modalities of pain. In this review, we will discuss the expression and functions of TRPV1 in various organ systems and highlight the consequences that might be associated with blocking the receptor.

Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1 is comprehensively elicited. The result is that the present state of knowledge can reasonably be described as a patch-work of insightful data where major deficits in knowledge remain and where meaningful general conclusions cannot be reliably drawn. This is unfortunate, given that this ion channel has been convincingly implicated in a wide range of physiological functions and pathological conditions. Moreover, the development of therapeutic strategies which target TRPV1 depends on the knowledge of this receptor's structure and its relationship with channel function. Here, we offer a description of the present state of knowledge in relation to this complex subject.

Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca2+) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca2+ influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca2+ overload. The ‘acute desensitization’ accounts for most of the reduction in responsiveness occurring within the first few (∼20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is ‘tachyphylaxis’, which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca2+ levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process.

The transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater than ∼43 °C, or to capsaicin, the pungent ingredient of hot chilli peppers. More importantly, however, it has been shown that TRPV1 plays a pivotal role in the development of the burning pain sensation associated with inflammation in peripheral tissues. More recently, there has been a virtual avalanche of sightings of TRPV1 on the anatomical landscape, coupled with association of TRPV1 with a wide range of non-pain-related physiological and pathological conditions. Here, we consider the continuously expanding set of functions in both health and disease which TRPV1 is understood to subserve at present. The widespread expression of TRPV1 in the human suggests that, in addition to the development of burning pain associated with acute exposure to heat or capsaicin, and with inflammation, TRPV1 may also be involved in an array of vitally important functions, such as those of the urinary tract, the respiratory and auditory systems. Moreover, TRPV1 may also be involved in the maintenance of body and cell homeostasis, metabolism, regulation of hair growth, and development of cancer. Thus, controlling TRPV1 function may possess the potential of providing exciting opportunities for therapeutic interventions. At the same time, however, the widespread distribution of these ion channels introduces a tremendous complication in developing a drug to serve in one disease context which may have profound implications for normal TRPV1 functioning in other non-pathological contexts.