TRP channels and their implications in metabolic diseases

The transient receptor potential (TRP) channel superfamily is composed of 28 nonselective cation channels that are ubiquitously expressed in many cell types and have considerable functional diversity. Although changes in TRP channel expression and function have been reported in cardiovascular disease and renal disorders, the pathogenic roles of TRP channels in metabolic diseases have not been systemically reviewed. In this review, we summarised the distribution of TRP channels in several metabolic tissues and discussed their roles in mediating and regulating various physiological and pathophysiological metabolic processes and diseases including diabetes, obesity, dyslipidaemia, metabolic syndrome, atherosclerosis, metabolic bone diseases and electrolyte disturbances. This review provides new insight into the involvement of TRP channels in the pathogenesis of metabolic disorders and implicates these channels as potential therapeutic targets for the management of metabolic diseases.     

Transient Receptor Potential (TRP) channels in T cells

The transient receptor potential (TRP) family of ion channels is widely expressed in many cell types and plays various physiological roles. Growing evidence suggests that certain TRP channels are functionally expressed in the immune system. Indeed, an increasing number of reports have demonstrated the functional expression of several TRP channels in innate and adaptive immune cells and have highlighted their critical role in the activation and function of these cells. However, very few reviews have been entirely dedicated to this subject. Here, we will summarize the recent findings with regards to TRP channel expression in T cells and discuss their emerging role as regulators of T cell activation and functions. Moreover, these studies suggest that beyond their pharmaceutical interest in pain management, certain TRP channels may represent potential novel therapeutic targets for various immune-related diseases.     

TRPpathies

Many human diseases are caused by mutations in ion channels. Dissecting the pathogenesis of these 'channelopathies' has yielded important insights into the regulation of vital biological processes by ions and has become a productive tool of modern ion channel biology. One of the best examples of a synergism between the clinical and basic science aspects of a modern biological topic is cystic fibrosis. Not only did the identification of the ion channel mutated in cystic fibrosis pinpoint the root cause of this disease, but it also has significantly advanced our understanding of basic biological processes as diverse as protein folding and epithelial fluid and electrolyte secretion. The list of confirmed 'channelopathies' is growing and several members of the TRP family of ion channels have been implicated in human diseases such as mucolipidosis type IV (MLIV), autosomal dominant polycystic kidney disease (ADPKD), familial focal segmental glomerulosclerosis (FSG), hypomagnesemia with secondary hypocalcaemia (HSH), and several forms of cancer. Analysing pathogenesis of the diseases linked to TRP dysregulation provides an exciting means of identifying novel functions of TRP channels.     

On the putative role of transient receptor potential cation channels in asthma

The mammalian transient receptor potential (TRP) superfamily consists of 28 mammalian TRP cation channels, which can be subdivided into six main subfamilies: the TRPC (' C anonical'), TRPV (' V anilloid'), TRPM (' M elastatin'), TRPP (' P olycystin'), TRPML (' M uco l ipin') and the TRPA (' A nkyrin') groups. Increasing evidence has accumulated during the previous few years that links TRP channels to the cause of several diseases or to critically influence and/or determine their progress. This review focuses on the possible role of TRP channels in the aetiology of asthmatic lung disease.     

Transient receptor potential channelopathies

In the past years, several hereditary diseases caused by defects in transient receptor potential channels (TRP) genes have been described. This review summarizes our current knowledge about TRP channelopathies and their possible pathomechanisms. Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated.     

A network perspective on unraveling the role of TRP channels in biology and disease

Transient receptor potential (TRP) channels are a large family of non-selective cation channels that mediate numerous physiological and pathophysiological processes; however, still largely unknown are the underlying molecular mechanisms. With data generated on an unprecedented scale, network-based approaches have been revolutionizing the way in which we understand biology and disease, discover disease genes, and develop therapeutic strategies. These circumstances have created opportunities to encounter TRP channel research to data-intensive science. In this review, we provide an introduction of network-based approaches in biomedical science, describe the current state of TRP channel network biology, and discuss the future direction of TRP channel research. Network perspective will facilitate the discovery of latent roles and underlying mechanisms of TRP channels in biology and disease.     

Invertebrate TRP proteins as functional models for mammalian channels

Transient receptor potential (TRP) channels constitute a large and diverse family of channel proteins that are expressed in many tissues and cell types in both vertebrates and invertebrates. While the biophysical features of many of the mammalian TRP channels have been described, relatively little is known about their biological roles. Invertebrate TRPs offer valuable genetic handles for characterizing the functions of these cation channels in vivo. Importantly, studies in model organisms can help to identify fundamental mechanisms involved in normal cellular functions and human disease. In this review, we give an overview of the different TRP channels known in the two most utilized invertebrate models, the nematode Caenorhabditis elegans and the fruit-fly Drosophila melanogaster, and discuss briefly the heuristic impact of these invertebrate channels with respect to TRP function in mammals.     

Function and regulation of TRP family channels in C. elegans

Seventeen transient receptor potential (TRP) family proteins are encoded by the C. elegans genome, and they cover all of the seven TRP subfamilies, including TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML. Classical forward and reverse genetic screens have isolated mutant alleles in every C. elegans trp gene, and their characterizations have revealed novel functions and regulatory mechanisms of TRP channels. For example, the TRPC channels TRP-1 and TRP-2 control nicotine-dependent behavior, while TRP-3, a sperm TRPC channel, is regulated by sperm activation and required for sperm–egg interactions during fertilization. Similar to their vertebrate counterparts, C. elegans TRPs function in sensory physiology. For instance, the TRPV channels OSM-9 and OCR-2 act in chemosensation, osmosensation, and touch sensation, the TRPA member TRPA-1 regulates touch sensation, while the TRPN channel TRP-4 mediates proprioception. Some C. elegans TRPM, TRPP, and TRPML members exhibit cellular functions similar to their vertebrate homologues and have provided insights into human diseases, including polycystic kidney disease, hypomagnesemia, and mucolipidosis type IV. The availability of a complete set of trp gene mutants in conjunction with its facile genetics makes C. elegans a powerful model for studying the function and regulation of TRP family channels in vivo.     

Ion channels and diseases

Ion channels play important roles in vital cellular signaling processes in both excitable and nonexcitable cells. Since 1987, a large number of channel genes have been cloned, and their biophysical properties, subunit stoichiometries, channel assemblies, and modulation by second messengers and ligands have been gradually elucidated. At present, more than ten ion channel genes have been identified as causing human hereditary diseases. Molecular techniques such as the positional cloning method are indispensable for finding new genes for channel-related diseases. Ion channels participate in the excitation-restoration of neurons and myocytes. Mutations of ion channels in these cells cause abnormal excitation and diseases such as long QT syndrome and ataxia. The second physiological function of ion channels, in addition to their regulation of cell excitability, is ion transport. Bartter's syndrome and Liddle's syndrome are due to abnormalities of ion transport. Most of these ion channel diseases are caused by loss of function, although some mutations are known to result in gain of function. The number of identified channel-related diseases is growing rapidly. Elucidation of the molecular basis of an ion channel disease not only provides new opportunities for early diagnosis and therapy for the disease but also provides clues to determine a previously unknown function of the ion channel.     

Expression of transient receptor potential (TRP) channel mRNAs in the mouse olfactory bulb

Transient receptor potential (TRP) channels are a large family of cation channels. The 28 TRP channel subtypes in rodent are divided into 6 subfamilies: TRPC1-7, TRPV1-6, TRPM1-8, TRPP2/3/5, TRPML1-3 and TRPA1. TRP channels are involved in peripheral olfactory transduction. Several TRPC channels are expressed in unidentified neurons in the main olfactory bulb (OB), but the expression of most TRP channels in the OB has not been investigated. The present study employed RT-PCR as an initial survey of the expression of TRP channel mRNAs in the mouse OB and in 3 cell types: external tufted, mitral and granule cells. All TRP channel mRNAs except TRPV5 were detected in OB tissue. Single cell RT-PCR revealed that external tufted, mitral and granule cell populations expressed in aggregate 14 TRP channel mRNAs encompassing members of all 6 subfamilies. These different OB neuron populations expressed 7–12 channel mRNAs. Common channel expression was more similar among external tufted and mitral cells than among these cells and granule cells. These results indicate that a large number of TRP channel subtypes are expressed in OB neurons, providing the molecular bases for these channels to regulate OB neuron activity and central olfactory processing.     

TRP channel proteins and signal transduction

TRP channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. This family was designated TRP because of a spontaneously occurring Drosophila mutant lacking TRP that responded to a continuous light with a transient receptor potential (hence TRP). In addition to responses to light, TRPs mediate responses to nerve growth factor, pheromones, olfaction, mechanical, chemical, temperature, pH, osmolarity, vasorelaxation of blood vessels, and metabolic stress. Furthermore, mutations in several members of TRP-related channel proteins are responsible for several diseases, such as several tumors and neurodegenerative disorders. TRP-related channel proteins are found in a variety of organisms, tissues, and cell types, including nonexcitable, smooth muscle, and neuronal cells. The large functional diversity of TRPs is also reflected in their diverse permeability to ions, although, in general, they are classified as nonselective cationic channels. The molecular domains that are conserved in all members of the TRP family constitute parts of the transmembrane domains and in most members also the ankyrin-like repeats at the NH2 terminal of the protein and a "TRP domain" at the COOH terminal, which is a highly conserved 25-amino acid stretch with still unknown function. All of the above features suggest that members of the TRP family are "special assignment" channels, which are recruited to diverse signaling pathways. The channels' roles and characteristics such as gating mechanism, regulation, and permeability are determined by evolution according to the specific functional requirements.     

Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels

Cellular redox status, regulated by production of reactive oxygen species (ROS), greatly contributes to the regulation of vascular smooth muscle cell contraction, migration, proliferation, and apoptosis by modulating the function of transient receptor potential (TRP) channels in the plasma membrane. ROS functionally interact with the channel protein via oxidizing the redox-sensitive residues, whereas nitric oxide (NO) regulates TRP channel function by cyclic GMP/protein kinase G-dependent and -independent pathways. Based on the structural differences among different TRP isoforms, the effects of ROS and NO are also different. In addition to regulating TRP channels in the plasma membrane, ROS and NO also modulate Ca(2+) release channels (e.g., IP(3) and ryanodine receptors) on the sarcoplasmic/endoplasmic reticulum membrane. This review aims at briefly describing (a) the role of TRP channels in receptor-operated and store-operated Ca(2+) entry, and (b) the role of ROS and redox status in regulating the function and structure of TRP channels.     

Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2

Members of the transient receptor potential (TRP) cation channel receptor family have unique sites of regulatory function in the kidney which enables them to promote regional vasodilatation and controlled Ca²⁺ influx into podocytes and tubular cells. Activated TRP vanilloid 1 receptor channels (TRPV1) have been found to elicit renoprotection in rodent models of acute kidney injury following ischaemia/reperfusion. Transient receptor potential cation channel, subfamily C, member 6 (TRPC6) in podocytes is involved in chronic proteinuric kidney disease, particularly in focal segmental glomerulosclerosis (FSGS). TRP vanilloid 4 receptor channels (TRPV4) are highly expressed in the kidney, where they induce Ca²⁺ influx into endothelial and tubular cells. TRP melastatin (TRPM2) non‐selective cation channels are expressed in the cytoplasm and intracellular organelles, where their inhibition ameliorates ischaemic renal pathology. Although some of their basic properties have been recently identified, the renovascular role of TRPV1, TRPV4, TRPC6 and TRPM2 channels in disease states such as obesity, hypertension and diabetes is largely unknown. In this review, we discuss recent evidence for TRPV1, TRPV4, TRPC6 and TRPM2 serving as potential targets for acute and chronic renoprotection in chronic vascular and metabolic disease.     

TRP channels and mechanosensory transduction: insights into the arterial myogenic response

Mechano-gated ion channels are implicated in a variety of key physiological functions ranging from touch sensitivity to arterial pressure regulation. Seminal work in prokaryotes and invertebrates provided strong evidence for the role of specific ion channels in volume regulation, touch sensitivity, or hearing, specifically the mechanosensitive channel subunits of large and small conductances (MscL and MscS), the mechanosensory channel subunits (MEC) and the transient receptor potential channel subunits (TRP). In mammals, recent studies further indicate that members of the TRP channel family may also be considered as possible candidate mechanosensors responding to either tension, flow, or changes in cell volume. However, contradictory results have challenged whether these TRP channels, including TRPC1 and TRPC6, are directly activated by mechanical stimulation. In the present review, we will focus on the mechanosensory function of TRP channels, discuss whether a direct or indirect mechanism is at play, and focus on the proposed role for these channels in the arterial myogenic response to changes in intraluminal pressure.     

The role of TRPM channels in cell death

Transient receptor potential (TRP) channels of the melastatin-like family (TRPM) play critical roles in mediating cellular responses to a wide range of physiological stimuli that, under certain situations, can induce cell death. To date, two TRPM family members, TRPM2 and TRPM7, have been implicated directly as central components of cell death pathways. TRPM2, a Ca²⁺-permeant, non-selective cation channel, senses and responds to oxidative stress levels in the cell. TRPM7 is required for cell viability and has been proposed recently to mediate stress-induced cell death in the central nervous system. We review here the evidence for the involvement of these TRPM channels in cell death processes and discuss the mechanisms by which TRPM channel activation occurs. The ability to attenuate expression levels and functionality of these channels is necessary to understand the involvement of TRPM in cell death and we evaluate current approaches for modulation of TRPM channel function. Finally, we discuss the possibility that TRPM channels may provide therapeutic targets for degenerative diseases involving oxidative stress-related pathologies including diabetes and Alzheimers disease.     

The history of TRP channels, a commentary and reflection

The transient receptor potential (TRP) family of cation channels has redefined our understanding of sensory physiology. In one animal or another, all senses depend on TRP channels. These include vision, taste, smell, hearing, and various forms of touch, including the ability to sense changes in temperature. The first trp gene was identified because it was disrupted in a Drosophila mutant with defective vision. However, there was no clue as to its biochemical function until the cloning, and analysis of the deduced amino acid sequence suggested that trp encoded a cation channel. This concept was further supported by subsequent electrophysiological studies, including alteration of its ion selectivity by an amino acid substitution within the pore loop. The study of TRP channels emerged as a field with the identification of mammalian homologs, some of which are direct sensors of environmental temperature. At least one TRP channel is activated downstream of a thermosensory signaling cascade, demonstrating that there exist two modes of activation, direct and indirect, through which TRP channels respond to changes in temperature. Mutations in many TRP channels result in disease, including a variety of sensory impairments.