Current Topics in Medicinal Chemistry - Volume 13, Issue 3, 2013

The disease of obesity is one of the greatest healthcare challenges of our time. The increasing urgency for effective treatment is driving an intensive search for new targets for anti-obesity drug discovery. The TRP channel super family represents a class of proteins now recognized to serve many functions in physiology related to maintenance of health and the development of diseases. A few of these might offer new potential for therapeutic intervention in obesity. Among the TRP channels, TRPV1 appears most closely associated with body weight homeostasis through its influence on energy expenditure. TRPM5 has been thoroughly characterized as a critical component of taste signaling and recently has been implicated in insulin release. Because of its role in taste signaling, we argue that drugs designed to modulate TRPM5 could be useful in controlling energy consumption by impacting taste sensory signals. As drug targets for obesity, both TRPV1 and TRPM5 offer the advantage of operating in compartments that could limit drug distribution to the site of action. The potential for other TRP channels as anti-obesity drug targets also is discussed.

Transient Receptor Potential (TRP) proteins constitute a family of cation channels with very diverse permeation and gating properties. Likewise they have a very diverse role in mammalian physiology ranging from sensory nerve endings, the cardiac muscle to immune cells. Increasing evidence has implicated TRP channels in the pathology of diabetes, both on the level of insulin release from the pancreatic ß cells and in secondary conditions such as diabetic neuropathy, nephropathy and vasculopathy. In this review we summarize these recent findings, which all together indicate that TRP channels are interesting drug targets for the treatment of patients suffering from diabetes.

Cardiac fibrosis is associated with most cardiac diseases. Fibrosis is an accumulation of excessive extracellular matrix proteins (ECM) synthesized by cardiac fibroblasts and myofibroblasts. Fibroblasts are the most prevalent cell type in the heart, comprising 75% of cardiac cells. Myofibroblasts are hardly present in healthy normal heart tissue, but appear abundantly in diseased hearts. Cardiac fibroblasts are activated by a variety of pathological stimuli, such as myocardial injury, oxidative stress, mechanical stretch, and elevated autocrine-paracrine mediators, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. A number of signaling pathways and bioactive molecules are involved and work in concert to activate fibroblasts and myofibroblasts in the fibrogenesis cascade. Fibroblasts and myofibroblasts are not only principal ECM producers, but also play a central role in fibrogenesis and myocardial remodeling in fibrotic heart disease. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of fibrosis and provide potential targets for developing antifibrotic drugs. Recent studies demonstrate that Ca2+ signal is essential for fibroblast proliferation, differentiation, and ECM-protein production. This review focuses on the recent advances in understanding molecular mechanisms of Ca2+ signaling in cardiac fibrogenesis, and potential role of Ca2+-permeable channels, in particular, the transient potential (TRP) channels in fibrotic heart disease. TRP channels are highly expressed in cardiac fibroblasts. TRPM7 has been shown to be essential in TGFβ1 mediated fibrogenesis, and TRPC3 has been demonstrated to play an essential role in regulating fibroblast function. Thus, the Ca2+-permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs.

Over the past 20 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge regarding the molecular basis of Ca2+ signals in cardiac myocytes. The functional significance of cardiac TRP channels is likely connected to the alteration of membrane potential or Ca2+ entry into a noncontractile compartment, where gene expression responsible for various cardiac diseases is induced. This review highlights some aspects of TRP channels with anticipated roles in cardiac disease. Evidence suggests that (a) increased activities of TRPC1, TRPC3, or TRPC6 are involved in the development of cardiac hypertrophy, where these TRPC channels act as unique sensors for a wide range of hypertrophic stimuli, and (b) mutations in TRPM4 are now recognized as causes of human cardiac conduction disorders. Ultimately, TRP channels may become novel pharmacological targets in the treatment of human cardiac disease.

In recent years, research on the roles of TRP channels in vascular function and disease has undergone a rapid expansion from tens of reports published in the early 2000s to several hundreds of papers published to date. Multiple TRP subtypes are expressed in vascular smooth muscle cells and endothelial cells, where they form diverse non-selective cation channels permeable to Ca2+. These channels mediate Ca2+ entry following receptor stimulation, Ca2+ store depletion and mechanical stimulation of vascular myocytes and endothelial cells. The complex molecular composition and signalling pathways leading to the activation of various vascular TRP channels and the growing evidence for their involvement in various vascular disorders, including dysregulation of vascular tone and hypertension, impaired endothelium-dependent vasodilatation, increased endothelial permeability, occlusive vascular disease, vascular injury and oxidative stress, are summarised and discussed in this review.

Novel effective therapeutic agents are actively sought for the treatment of a broad spectrum of respiratory diseases which collectively significantly impact on mortality, morbidity and quality of life of hundreds of millions of people world-wide. These include asthma, allergic rhinitis, chronic obstructive pulmonary disease, cough, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and acute lung injury. TRP channels are broadly distributed throughout the respiratory tract and play an important physiological role in sensing and subsequently responding to a wide variety of stimuli, for example temperature, osmolarity and oxidant stress. In the context of respiratory disease however TRP channel function may be altered, eg: under conditions of oxidative stress, inflammation, hypoxia and mechanical stress. In addition there is evidence that the expression/activity of TRP channels can be affected in the disease setting. Modulators of TRP channel function are therefore under investigation for a range of diseases including disorders of the respiratory system. Several excellent review articles have discussed in detail evidence that modulation of specific TRP channels may be of benefit in specific respiratory diseases. In this article we have taken the approach of reviewing evidence that modulation of TRP channel function may be able to affect common and over-lapping characteristic features of respiratory diseases, for example bronchoconstriction, airways hyper-responsiveness, cough, airways inflammation, mucus hyper-secretion, exacerbations, lung injury, hypoxia and airways re-modelling. The therapeutic potential of TRP channel modulators, the status of these agents in the clinic along with the challenges posed in this rapidly advancing field are also discussed in this review.

Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis present a significant medical challenge in the modern world. Recent evidence indicates that perturbation of neuronal Ca2+ homeostasis is involved in the pathogenesis of these neurodegenerative disorders. Transient receptor potential (TRP) channels are non-selective cation channels that are expressed in various cell types and tissues, and play an important role in regulating Ca2+ signaling in both non-neuronal and neuronal cells. TRP channels are related to the onset or progression of several diseases, and defects in the genes encoding TRP channels (so-called “TRP channelopathies”) underlie certain neurodegenerative disorders due to their abnormal Ca2+ signaling properties. In this article, we review recent findings regarding the relationship between TRPs and neurodegenerative disorders, and discuss the therapeutic potential of targeting TRP channels pharmacologically.

Transient receptor potential (TRP) cation channels are an emerging field of research in dermatology. Beyond their classical role in skin sensory perception, TRPs are involved in various cutaneous functions that include keratinocyte differentiation, apoptosis and melanocyte pigmentation. In addition, they have a role as pharmacological targets in many inflammatory skin diseases including psoriasis, chronic itch, hair disorders and skin cancers. Moreover, mutations in TRPs have recently been related to rare skin conditions such as Olmsted syndrome. This review will cover the role of TRPs in dermatologic conditions with special emphasis on itch and skin inflammatory diseases.

Transient Receptor Potential (TRP) channels affect several inflammatory and neoplastic conditions. About thirty TRPs have been identified to date and divided into seven families: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPML (Mucolipin), TRPP (Polycystin), and TRPA (Ankyrin transmembrane protein) and TRPN (NomPClike). Among these, the TRPC, TRPM, and TRPV families have been mainly correlated with malignant growth and progression. The aim of this review is to summarize data reported so far on the expression and functional role of TRP channels in different types of cancers. TRP channels have been recently implicated in the triggering of enhanced proliferation, aberrant differentiation, and resistance to apoptotic cell death, leading to uncontrolled tumor growth and progression. Depending on cancer stage, up and down-regulation of TRP mRNAs and protein expression have been reported. These changes have been shown to exhibit cancer promoting (oncogenic) or inhibiting/delaying (tumor suppressor) effects. We are only at the beginning, and more detailed study on the physiopathologic role of TRP channels is required to understand how the deregulation of TRP channel expression and function contributes to tumor development and progression. It is hoped that greater knowledge about TRP biology will enable future development of new chemotherapeutic agents for specific TRP targets, and the use of TRP channels as evaluable markers in diagnostic and/or prognostic analysis.

During inflammation, several Transient Receptor Potential (TRP) channels are directly or indirectly activated by inflammatory signaling molecules and microenvironmental changes including heat, oxidative conditions or low pH. In either case, specific TRP isoforms participate in chains of pro- or anti-inflammatory signaling cascades often including activation of transcription factors, protein kinases and phospholipases, which result in signal integration or amplification. In a few cases, their potentials as therapeutic targets for inflammatory conditions like pruritis, cystitis, dermatitis, asthma among other conditions are investigated pre-clinically or clinically by pioneering academic groups and industries. Significant efforts are still devoted to the understanding of the detailed physiological roles played by TRP channels during inflammation. This review intends to summarize key biological findings and reports of drug discovery activities when available, in an overview of the current status and recent developments in the field.

The Drosophila trp homologue Transient Receptor Potential (TRP) cation channels are ubiquitous in most species and cell types. The functional TRP subclasses TRPC, TRPV and TRPP gate Ca2+ and other cations in mammalian tissues, including the kidney. It is now clear that TRP channels play an important role in renal physiology and in certain genetic disorders of the kidney. Hence, there is considerable interest in targeting mutated or dysfunctional TRP channels in an effort to treat such diseases. Transcellular epithelial cell Ca2+ reabsorption occurs in the distal tubule via luminal TRPV5/V6 channels. Indeed, TRPV5 KO mice display phenotypic defects of renal disease, including hypercalciuria and impaired bone mineral density. Similar to Ca2+, Mg2+ transcellular reabsorption occurs in the distal convoluted tubule via apical TRPM6/TRPM7 channels. TRPC6 is a component of the glomerular podocyte “slit diaphragm” and its autosomic dominant mutation has been linked to a familial, steroid-resistant form of nephrotic syndrome. A more common inherited disorder of the tubular epithelium, autosomal dominant polycystic kidney disease (ADPKD), is at least in part related to mutation of polycystin 2 (PC2), a protein encoded by the PKD2 gene. PC2 is now identified as TRPP2, a Ca2+-permeable non-selective cation channel located on the cilia of tubular epithelial cells. TRP-related ion transport may also play a role in the pathogenesis of arterial systemic and/or pulmonary hypertension through regulation of vascular smooth muscle contraction, renal perfusion/hemodynamics, as well as the total body balance of divalent cations. Thus, multiple renal TRP channels are potential targets for pharmacological intervention aimed at preventing or attenuating the burden of chronic kidney disease.

The transient receptor potential (TRP) superfamily consists of a large number of cation channels permeable to both monovalent and divalent cations. The 28 mammalian TRP channels can be divided into seven subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPN (no mechanopotential, NOMP) and the TRPA (ankyrin) groups. TRP channels are widely expressed in several cell types in every tissue and play a critical role in the regulation of various cell functions. Altogether these channels function as sensory transducers and detect chemical, thermal and mechanical stimuli. Endogenous substances acting on TRP channels can be released during the early stage of some pathological conditions. These substances can affect TRP channel functions and lead to the progression of diseases such as inflammation and chronic pain. For example, endogenous lipids, such as unsaturated fatty acids and their cyclooxygenase, lipoxygenase or epoxygenase related metabolites, were shown to modulate TRP channel activity by direct binding. Other lipidergic ligands include isoprene derivatives (e.g. diacylglycerol, lysophospholipids and resolvine) which play diverse activity on different TRP channels. This review focuses on lipidergic mediators which affect TRP channel activity. Opportunities to exploit TRP channels for novel therapeutic strategies will be discussed.