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BBA - Molecular Basis of Disease (v.1772, #8)

Editorial Board (pp. ii).

TRP channels in disease by Bernd Nilius (pp. 805-812).

“Transient receptor potential” cation channels (TRP channels) play a unique role as cell sensors, are involved in a plethora of Ca²⁺-mediated cell functions, and play a role as “gate-keepers” in many homeostatic processes such as Ca²⁺ and Mg²⁺ reabsorption. The variety of functions to which TRP channels contribute and the polymodal character of their activation predict that failures in correct channel gating or permeation will likely contribute to complex pathophysiological mechanisms. Dysfunctions of TRPs cause human diseases but are also involved in a complex manner to contribute and determine the progress of several diseases. Contributions to this special issue discuss channelopathias for which mutations in TRP channels that induce “loss-“ or “gain-of-function” of the channel and can be considered “disease-causing” have been identified. The role of TRPs will be further elucidated in complex diseases of the intestinal, renal, urogenital, respiratory, and cardiovascular systems. Finally, the role of TRPs will be discussed in neuronal diseases and neurodegenerative disorders.

Keywords: TRP channel; Channelopathy; Hereditary disease; Systemic disease; Transgenic model

TRPM6 and TRPM7—Gatekeepers of human magnesium metabolism by Karl P. Schlingmann; Siegfried Waldegger; Martin Konrad; Vladimir Chubanov; Thomas Gudermann (pp. 813-821).

Human magnesium homeostasis primarily depends on the balance between intestinal absorption and renal excretion. Magnesium transport processes in both organ systems – next to passive paracellular magnesium flux – involve active transcellular magnesium transport consisting of an apical uptake into the epithelial cell and a basolateral extrusion into the interstitium. Whereas the mechanism of basolateral magnesium extrusion remains unknown, recent molecular genetic studies in patients with hereditary hypomagnesemia helped gain insight into the molecular nature of apical magnesium entry into intestinal brush border and renal tubular epithelial cells. Patients with Hypomagnesemia with Secondary Hypocalcemia (HSH), a primary defect in intestinal magnesium absorption, were found to carry mutations in TRPM6, a member of the melastatin-related subfamily of transient receptor potential (TRP) ion channels. Before, a close homologue of TRPM6, TRPM7, had been characterized as a magnesium and calcium permeable ion channel vital for cellular magnesium homeostasis. Both proteins share the unique feature of an ion channel fused to a kinase domain with homology to the family of atypical alpha kinases. The aim of this review is to summarize the data emerging from clinical and molecular genetic studies as well as from electrophysiologic and biochemical studies on these fascinating two new proteins and their role in human magnesium metabolism.

Keywords: Magnesium; Hypomagnesemia; TRPM6; TRPM7; Channel kinase; Transient receptor potential channel

TRPM7 and TRPM2—Candidate susceptibility genes for Western Pacific ALS and PD? by Meredith C. Hermosura; Ralph M. Garruto (pp. 822-835).

Recent findings implicating TRPM7 and TRPM2 in oxidative stress-induced neuronal death thrust these channels into the spotlight as possible therapeutic targets for neurodegenerative diseases. In this review, we describe how the functional properties of TRPM7 and TRPM2 are interconnected with calcium (Ca²⁺) and magnesium (Mg²⁺) homeostasis, oxidative stress, mitochondrial dysfunction, and immune mechanisms, all principal suspects in neurodegeneration. We focus our discussion on Western Pacific Amyotrophic Lateral Sclerosis (ALS) and Parkinsonism Dementia (PD) because extensive studies conducted over the years strongly suggest that these diseases are ideal candidates for a gene-environment model of etiology. The unique mineral environment identified in connection with Western Pacific ALS and PD, low Mg²⁺ and Ca²⁺, yet high in transition metals, creates a condition that could affect the proper function of these two channels.

Keywords: TRPM7; TRPM2; Western Pacific ALS; Parkinsonism Dementia; Oxidative stress; Neurodegeneration; Ca; ²⁺; and Mg; ²⁺; homeostasis; Mitochondrial dysfunction; Microglial activation

TRPP2 and autosomal dominant polycystic kidney disease by Michael Köttgen (pp. 836-850).

Mutations in TRPP2 (polycystin-2) cause autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder characterized by progressive development of fluid-filled cysts in the kidney and other organs. TRPP2 is a Ca²⁺-permeable nonselective cation channel that displays an amazing functional versatility at the cellular level. It has been implicated in the regulation of diverse physiological functions including mechanosensation, cell proliferation, polarity, and apoptosis. TRPP2 localizes to different subcellular compartments, such as the endoplasmic reticulum (ER), the plasma membrane and the primary cilium. The channel appears to have distinct functions in different subcellular compartments. This functional compartmentalization is thought to contribute to the observed versatility and specificity of TRPP2-mediated Ca²⁺ signaling. In the primary cilium, TRPP2 has been suggested to function as a mechanosensitive channel that detects fluid flow in the renal tubule lumen, supporting the proposed role of the primary cilium as the unifying pathogenic concept for cystic kidney disease. This review summarizes the known and emerging functions of TRPP2, focusing on the question of how channel function translates into complex morphogenetic programs regulating tubular structure.

Keywords: Polycystic kidney disease; PKD2; Polycystin-2; Cilia; Ca; ²⁺; ADPKD

TRPML and lysosomal function by David A. Zeevi; Ayala Frumkin; Gideon Bach (pp. 851-858).

Mucolipin 1 (MLN1), also known as TRPML1, is a member of the mucolipin family. The mucolipins are the only lysosomal proteins within the TRP superfamily. Mutations in the gene coding for TRPML1 result in a lysosomal storage disorder (LSD). This review summarizes the current knowledge related to this protein and the rest of the mucolipin family.

Keywords: Lysosomal storage disorder; Mucolipin protein family; Endocytosis and lysosomal function; Mucolipidosis

TRPC6 and FSGS: The latest TRP channelopathy by Nirvan Mukerji; Tirupapuliyur V. Damodaran; Michelle P. Winn (pp. 859-868).

Focal and segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in children and adults throughout the world. In the past 50 years, significant advances have been made in the identification and characterization of familial forms of nephrotic syndrome and FSGS. Resultant to these pursuits, several podocyte structural proteins such as nephrin, podocin, alpha-actinin 4 (ACTN4), and CD2-associated protein (CD2AP) have emerged to provide critical insight into the pathogenesis of hereditary nephrotic syndromes. The latest advance in familial FSGS has been the discovery of a mutant form of canonical transient receptor potential cation channel 6 (TRPC6), which causes an increase in calcium transients and essentially a gain of function in this cation channel located on the podocyte cell membrane. The TRP ion channel family is a diverse group of cation channels united by a common primary structure which contains six membrane-spanning domains, with both carboxy and amino termini located intracellularly. TRP channels are unique in their ability to activate independently of membrane depolarization. TRPC6 channels have been shown to be activated via phospholipase C stimulation. The mechanisms by which mutant TRPC6 causes an increase in intracellular calcium and leads to glomerulosclerosis are unknown. Mutant TRPC6 may affect critical interactions with the aforementioned podocyte structural proteins, leading to abnormalities in the slit diaphragm or podocyte foot processes. Mutant TRPC6 may also amplify injurious signals mediated by Ang II, a common final pathway of podocyte apoptosis in various mammalian species. Current evidence also suggests that blocking TRPC6 channels may be of therapeutic benefit in idiopathic FSGS, a disease with a generally poor prognosis. Preliminary experiments reveal the commonly used immunosuppressive agent FK-506 can inhibit TRPC6 activity in vivo. This creates the exciting possibility that blocking TRPC6 channels within the podocyte may translate into long-lasting clinical benefits in patients with FSGS.

Keywords: Familial focal segmental glomerulosclerosis; Familial nephropathy; Genetic; Kidney; Hereditary; TRPC6; Podocin; Nephrin; ACTN4; CD2AP

The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis by Rodger A. Liddle (pp. 869-878).

Premature activation of digestive enzymes within the pancreas which leads to autodigestion of the gland is an early step in the pathogenesis of pancreatitis. Pancreatic injury is followed by other manifestations of inflammation including plasma extravasation, edema, and neutrophil infiltration which constitute the features of pancreatitis. Recent studies indicate that neural innervation of the pancreas may play an important role in the initiation and maintenance of the inflammatory response to injury. The pancreas is innervated by vagal, sympathetic and parasympathetic neurons, as well as sensory neurons. Activation of pancreatic primary sensory neurons causes the release of inflammatory neuropeptides both in the spinal cord to signal pain and in the pancreas itself where they produce plasma extravasation and neutrophil infiltration. Recent studies indicate that primary sensory neurons of the pancreas express transient receptor potential V1 (TRPV1) channels whose activation induces pancreatic inflammation. Moreover, blockade of these TRP channels significantly ameliorates experimental pancreatitis. This review describes our current understanding of the role of TRPV1 channels in pancreatitis and illustrates how this mechanism might be used to direct future treatments of pancreatic diseases.

Keywords: Acute pancreatitis; Chronic pancreatitis; Experimental pancreatitis; Neurogenic inflammation; Substance P; Vanilloid receptor; VR1; Capsaicin receptor

TRPs in bladder diseases by Lori A. Birder (pp. 879-884).

This review attempts to provide an overview of the current knowledge of TRP proteins and their possible role in bladder function and disease. At present, there are 28 transient receptor potential (TRP) channels (subdivided into 7 categories or families) which are involved in a number of functions [G.A. Hicks, TRP channels as therapeutic targets: hot property, or time to cool down? Neurogastroenterology and Motility 18, (2006) 590–594., J.D. Levine, N. Alessandri-Haber, TRP channels: targets for the relief of pain, Biochimica et Biophysica Acta 1772, (2007) 989–1003.]. Of those belonging to the group 1 subfamily, a number of TRPV, TRPM and TRPA proteins associated with osmoregulation, thermal, chemical and mechanical signaling mechanisms have been shown to be expressed within the lower urinary tract. Though the biological role of many of these channels in urinary bladder function still remains elusive, TRPV1 is by far the best characterized and is thought to be involved in a number of bladder disorders [A. Szallasi, P.M. Blumberg, Vanilloid (Capsaicin) Receptors and Mechanisms, Pharmacological Reviews 51, (1999) 150–221., I. Nagy, P. Santha, G. Jansco, L. Urban, The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology, European Journal of Pharmacology 500, (2004) 351–369.].

Keywords: Capsaicin; Urothelium; Non-neuronal; Urinary bladder; neurogenic bladder

Involvement of transient receptor potential proteins in cardiac hypertrophy by Romain Guinamard; Patrick Bois (pp. 885-894).

Cardiac hypertrophy is an adaptive process that occurs in response to increased physical stress on the heart. Hypertrophy, which may be induced by hypertension among other factors, is characterized by an increase in left ventricular mass and an associated increase in force production capacity. However, as sustained cardiac hypertrophy may lead to heart failure and sudden death, an understanding of the molecular processes involved in both the onset and consequences of hypertrophy is of significant importance. Calcium is a key player in the process underlying the development of cardiac hypertrophy. Recently, several Transient Receptor Potential proteins (TRPs), including calcium-permeable and calcium-regulated ion channels, have been shown to be related to various aspects of cardiac hypertrophy. TRPs are implicated in the development of cardiac hypertrophy (TRPC1, TRPC3, TRPC6), the electrophysiological perturbations associated with hypertrophy (TRPM4) and the progression to heart failure (TRPC7). This review describes the major characteristics of cardiac hypertrophy and focuses on the roles of TRPs in the physiological processes underlying hypertrophy.

Keywords: Cation channel; Cardiomyocyte; Heart; Hypertrophy; TRP; TRPC1; TRPC3; TRPM4

TRP channels in hypertension by Amy L. Firth; Carmelle V. Remillard; Jason X.-J. Yuan (pp. 895-906).

Pulmonary and systemic arterial hypertension are associated with profound alterations in Ca²⁺ homeostasis and smooth muscle cell proliferation. A novel class of non-selective cation channels, the transient receptor potential (TRP) channels, have emerged at the forefront of research into hypertensive disease states. TRP channels are identified as molecular correlates for receptor-operated and store-operated cation channels in the vasculature. Over 10 TRP isoforms are identified at the mRNA and protein expression levels in the vasculature. Current research implicates upregulation of specific TRP isoforms to be associated with increased Ca²⁺ influx, characteristic of vasoconstriction and vascular smooth muscle cell proliferation. TRP channels are implicated as Ca²⁺ entry pathways in pulmonary hypertension and essential hypertension. Caveolae have recently emerged as membrane microdomains in which TRP channels may be co-localized with the endoplasmic reticulum in both smooth muscle and endothelial cells. Such enhanced expression and function of TRP channels and their localization in caveolae in pathophysiological hypertensive disease states highlights their importance as potential targets for pharmacological intervention.

Keywords: Abbreviations; CCE; capacitative Ca; ²⁺; entry; EC; endothelial cell; NCX; Na; ⁺; –Ca; ²⁺; exchanger; PAEC; pulmonary artery endothelial cell; PAH; pulmonary arterial hypertension; PASMC; pulmonary artery smooth muscle cell; ROC; receptor-operated Ca; ²⁺; channel; SERCA; sarcoplasmic/endoplasmic reticulum Ca; ²⁺; -ATPase; SMC; smooth muscle cell; SOC; store-operated Ca; ²⁺; channel; SR; sarcoplasmic reticulum; TRP; transient receptor potential channelPulmonary arterial hypertension; Essential hypertension; Transient receptor potential channels; Ca; ²⁺; Proliferation

TRP channels in endothelial function and dysfunction by Hiu-Yee Kwan; Yu Huang; Xiaoqiang Yao (pp. 907-914).

Endothelial cells produce various factors that regulate vascular tone, vascular permeability, angiogenesis, and inflammatory responses. The dysfunction of endothelial cells is believed to be the major culprit in various cardiovascular diseases, including hypertension, atherosclerosis, heart and renal failure, coronary syndrome, thrombosis, and diabetes. Endothelial cells express multiple transient receptor potential (TRP) channel isoforms, the activity of which serves to modulate cytosolic Ca²⁺ levels ([Ca²⁺]_i) and regulate membrane potential, both of which affect various physiological processes. The malfunction and dysregulation of TRP channels is associated with endothelial dysfunction, which is reflected by decreased nitric oxide (NO) bioavailability, inappropriate regulation of vascular smooth muscle tonicity, endothelial barrier dysfunction, increased oxidative damage, impaired anti-thrombogenic properties, and perturbed angiogenic competence. Evidence suggests that dysregulation of TRPC4 and -C1 results in vascular endothelial barrier dysfunction; malfunction of TRPP1 and -P2 impairs endothelial NO synthase; the reduced expression or activity of TRPC4 and -V1 impairs agonist-induced vascular relaxation; the decreased activity of TRPV4 reduces flow-induced vascular responses; and the activity of TRPC3 and -C4 is associated with oxidative stress-induced endothelial damage. In this review, we present a comprehensive summary of the literature on the role of TRP channels in endothelial cells, with an emphasis on endothelial dysfunction.

Role of TRPV receptors in respiratory diseases by Yanlin Jia; Lu-Yuan Lee (pp. 915-927).

Transient receptor potential vanilloid type channels (TRPVs) are expressed in several cell types in human and animal lungs. Increasing evidence has demonstrated important roles of these cation channels, particularly TRPV1 and TRPV4, in the regulation of airway function. These TRPVs can be activated by a number of endogenous substances (hydrogen ion, certain lipoxygenase products, etc.) and changes in physiological conditions (e.g., temperature, osmolarity, etc.). Activation of these channels can evoke Ca²⁺ influx and excitation of the neuron. TRPV1 channels are generally expressed in non-myelinated afferents innervating the airways and lungs, which also contain sensory neuropeptides such as tachykinins. Upon stimulation, these sensory nerves elicit centrally-mediated reflex responses as well as local release of tachykinins, and result in cough, airway irritation, reflex bronchoconstriction and neurogenic inflammation in the airways. Recent studies clearly demonstrated that the excitability of TRPV1 channels is up-regulated by certain autacoids (e.g., prostaglandin E₂, bradykinin) released during airway inflammatory reaction. Under these conditions, the TRPV1 can be activated by a slight increase in airway temperature or tissue acidity. Indirect evidence also suggests that TRPV channels may play a part in the pathogenesis of certain respiratory diseases such as asthma and chronic cough. Therefore, the potential use of TRPV antagonists as a novel therapy for these diseases certainly merits further investigation.

Keywords: TRPV; Respiratory disease; Neuropeptide; Inflammation; Chronic cough

TRP channels in kidney disease by Yu-Juei Hsu; Joost G.J. Hoenderop; René J.M. Bindels (pp. 928-936).

Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell functions and are considered to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in kidney along different parts of the nephron and growing evidence suggest that these channels are involved in hereditary, as well as acquired kidney disorders. TRPC6, TRPM6, and TRPP2 have been implicated in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively. In addition, the highly Ca²⁺-selective channel, TRPV5, contributes to several acquired mineral (dys)regulation, such as diabetes mellitus (DM), acid–base disorders, diuretics, immunosuppressant agents, and vitamin D analogues-associated Ca²⁺ imbalance whereas TRPV4 may function as an osmoreceptor in kidney and participate in the regulation of sodium and water balance. This review presents an overview of the current knowledge concerning the distribution of TRP channels in kidney and their possible roles in renal physiology and kidney diseases.

Keywords: Transient receptor potential channel; Calcium, magnesium; Ion transport; Reabsorption

TRP channels in cancer by Natalia Prevarskaya; Lei Zhang; Greg Barritt (pp. 937-946).

The progression of cells from a normal differentiated state in which rates of proliferation and apoptosis are balanced to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signalling proteins and the evolution and clonal selection of more aggressive cell phenotypes. These events are associated with changes in the expression of numerous other proteins. This process of tumorigenesis involves the altered expression of one or more TRP proteins, depending on the nature of the cancer. The most clearly described changes are those involving TRPM8, TRPV6 and TRPM1. Expression of TRPM8 is substantially increased in androgen-dependent prostate cancer cells, but is decreased in androgen independent and metastatic prostate cancer. TRPM8 expression is regulated, in part, by androgens, most likely through androgen response elements in the TRPM8 promoter region. TRPM8 channels are involved in the regulation of cell proliferation and apoptosis. Expression of TRPV6 is also increased in prostate cancer and in a number of other cancers. In contrast to TRPM8, expression of TRPV6 is not directly regulated by androgens. TRPM1 is highly expressed in early stage melanomas but its expression declines with increases in the degree of aggressiveness of the melanoma. The expression of TRPV1, TRPC1, TRPC6, TRPM4, and TRPM5 is also increased in some cancers. The level of expression of TRPM8 and TRPV6 in prostate cancer, and of TRPM1 in melanomas, potentially provides a good prognostic marker for predicting the course of the cancer in individuals. The Drosophila melanogaster, TRPL, and the TRPV1 and TRPM8 proteins, have been used to try to develop strategies to selectively kill cancer cells by activating Ca²⁺ and Na⁺ entry, producing a sustained increase in the cytoplasmic concentration of these ions, and subsequent cell death by apoptosis and necrosis. TRPV1 is expressed in neurones involved in sensing cancer pain, and is a potential target for pharmacological inhibition of cancer pain in bone metastases, pancreatic cancer and most likely in other cancers. Further studies are required to assess which other TRP proteins are associated with the development and progression of cancer, what roles TRP proteins play in this process, and to develop further knowledge of TRP proteins as targets for pharmaceutical intervention and targeting in cancer.

Keywords: Cancer; TRP channels; Intracellular Ca; ²⁺; Sensory nerves; Cell death; Hormone

Non-selective cation channels, transient receptor potential channels and ischemic stroke by J. Marc Simard; Kirill V. Tarasov; Volodymyr Gerzanich (pp. 947-957).

Several pathways to neural cell death are involved in ischemic stroke, and all require monovalent or divalent cation influx, implicating non-selective cation (NC) channels. NC channels are also likely to be involved in the dysfunction of vascular endothelial cells that leads to formation of edema following cerebral ischemia. Two newly described NC channels have emerged as potential participants in ischemic stroke, the acid sensing ion channel (ASIC), and the sulfonylurea receptor-1 (SUR1)-regulated NC_Ca-ATP channel. Non-specific blockers of NC channels, including pinokalant (LOE 908 MS) and rimonabant (SR141716A), have beneficial effects in rodent models of ischemic stroke. Evidence is accumulating that NC channels formed by members of the transient receptor potential (TRP) family are also up-regulated in ischemic stroke and may play a direct role in calcium-mediated neuronal death. The nascent field of NC channels, including TRP channels, in ischemic stroke is poised to provide novel mechanistic insights and therapeutic strategies for this often devastating human condition.

Keywords: Cation channel; Acid sensing ion channel; NC; _Ca-ATP; channel; Transient receptor potential; Cerebral ischemia; Stroke

Transient receptor potential channels in Alzheimer's disease by Shinichiro Yamamoto; Teruaki Wajima; Yuji Hara; Motohiro Nishida; Yasuo Mori (pp. 958-967).

Cognitive impairment and emotional disturbances in Alzheimer's disease (AD) result from the degeneration of synapses and neuronal death in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid β-peptide (Aβ) in the brain. Aβ can render neurons vulnerable to excitotoxicity and apoptosis by disruption of cellular Ca²⁺ homeostasis and neurotoxic factors including reactive oxygen species (ROS), nitric oxide (NO), and cytokines. Many lines of evidence have suggested that transient receptor potential (TRP) channels consisting of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) are involved in Ca²⁺ homeostasis disruption. Thus, emerging evidence of the pathophysiological role of TRP channels has yielded promising candidates for molecular entities mediating Ca²⁺ homeostasis disruption in AD. In this review, we focus on the TRP channels in AD and highlight some TRP “suspects” for which a role in AD can be anticipated. An understanding of the involvement of TRP channels in AD may lead to the development of new target therapies.

Keywords: TRP; AD; Aβ; ROS; Ca; ²⁺; homeostasis disruption

TRP's: Links to schizophrenia? by Loris A. Chahl (pp. 968-977).

Schizophrenia is a chronic psychiatric disorder the cause of which is unknown. It is considered to be a neurodevelopmental disorder that results from an interaction of genetic and environmental factors. Direct evidence for links between schizophrenia and TRP channels is lacking. However, several aspects of the pathophysiology of the disorder point to a possible involvement of TRP channels. In this review evidence for links between TRP channels and schizophrenia with respect to neurodevelopment, dopaminergic and cannabinoid systems, thermoregulation, and sensory processes, is discussed. Investigation of these links holds the prospect of a new understanding of schizophrenia with resultant therapeutic advances.

Keywords: TRP channels; Schizophrenia; Capsaicin; Sensory system; Thermoregulation; Dopamine

TRP channels and pain by Daniel N. Cortright; James E. Krause; Daniel C. Broom (pp. 978-988).

Since the molecular identification of the capsaicin receptor, now known as TRPV1, transient receptor potential (TRP) channels have occupied an important place in the understanding of sensory nerve function in the context of pain. Several TRP channels exhibit sensitivity to substances previously known to cause pain or pain-like sensations; these include cinnamaldehyde, menthol, gingerol, and icillin. Many TRP channels also exhibit significant sensitivity to increases or decreases in temperature. Some TRP channels are sensitized in vitro by the activation of other receptors such that these channels may be activated by processes, such as inflammation that result in pain. TRP channels are suggested to be involved in processes as diverse as sensory neuron activation events, neurotransmitter release and action in the spinal cord, and release of inflammatory mediators. These functions strongly suggest that specific and selective inhibition of TRP channel activity will be of use in alleviating pain.

Keywords: Pain; TRPV1; TRPA1; Mechanical hypersensitivity; Nociceptive processing; Inflammation

TRP channels: Targets for the relief of pain by Jon D. Levine; Nicole Alessandri-Haber (pp. 989-1003).

Patients with inflammatory or neuropathic pain experience hypersensitivity to mechanical, thermal and/or chemical stimuli. Given the diverse etiologies and molecular mechanisms of these pain syndromes, an approach to developing successful therapies may be to target ion channels that contribute to the detection of thermal, mechanical and chemical stimuli and promote the sensitization and activation of nociceptors. Transient Receptor Potential (TRP) channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that contribute to the detection of physical stimuli. Six TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1) have been shown to be expressed in primary afferent nociceptors, pain sensing neurons, where they act as transducers for thermal, chemical and mechanical stimuli. This short review focuses on their contribution to pain hypersensitivity associated with peripheral inflammatory and neuropathic pain states.

Keywords: TRP channels; Pain; Nociceptors; Inflammation; Neuropathy

TRP channels as novel players in the pathogenesis and therapy of itch by Tamás Bíró; Balázs I. Tóth; Rita Marincsák; Nóra Dobrosi; Tamás Géczy; Ralf Paus (pp. 1004-1021).

Itch (pruritus) is a sensory phenomenon characterized by a (usually) negative affective component and the initiation of a special behavioral act, i.e. scratching. Older studies predominantly have interpreted itch as a type of pain. Recent neurophysiological findings, however, have provided compelling evidence that itch (although it indeed has intimate connections to pain) rather needs to be understood as a separate sensory modality. Therefore, a novel pruriceptive system has been proposed, within which itch-inducing peripheral mediators (pruritogens), itch-selective receptors (pruriceptors), sensory afferents and spinal cord neurons, and defined, itch-processing central nervous system regions display complex, layered responses to itch. In this review, we begin with a current overview on the neurophysiology of pruritus, and distinguish it from that of pain. We then focus on the functional characteristics of the large family of transient receptor potential (TRP) channels in skin-coupled sensory mechanisms, including itch and pain. In particular, we argue that – due to their expression patterns, activation mechanisms, regulatory roles, and pharmacological sensitivities – certain thermosensitive TRP channels are key players in pruritus pathogenesis. We close by proposing a novel, TRP-centered concept of pruritus pathogenesis and sketch important future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

Keywords: Itch; Pruriceptive pruritus; Pruritogens; TRP channels

TRP channels as candidates for hearing and balance abnormalities in vertebrates by Math P. Cuajungco; Christian Grimm; Stefan Heller (pp. 1022-1027).

In this review, we summarize the potential functional roles of transient receptor potential (TRP) channels in the vertebrate inner ear. The history of TRP channels in hearing and balance is characterized at great length by the hunt for the elusive transduction channel of sensory hair cells. Such pursuit has not resulted in unequivocal identification of the transduction channel, but nevertheless revealed a number of candidates, such as TRPV4, TRPN1, TRPA1, and TRPML3. Much of the circumstantial evidence indicates that these TRP channels potentially play significant roles in inner ear physiology. Based on mutations in the corresponding mouse genes, TRPV4 and TRPML3 are possible candidates for human hearing, and potentially also balance disorders. We further discuss the role of the invertebrate TRP channels Nanchung, Inactive, and TRPN1 and how the functional analysis of these channels provides a link to vertebrate hearing and balance. In summary, only a few TRP channels have been analyzed thus far for a prospective role in the inner ear, and this makes the search for additional TRPs associated with inner ear function quite a tantalizing endeavor.

Keywords: Inner ear; Cochlea; Hearing loss; Hair cell; Auditory

TRPML3 and hearing loss in the varitint-waddler mouse by Margaret Atiba-Davies; Konrad Noben-Trauth (pp. 1028-1031).

TRPML3 (also known as mucolipin-3, MCOLN3) belongs to the small family of TRPML ion channel proteins. The mammalian Trpml3 gene encodes a protein of 553 amino acids with short amino and carboxy termini and a transient receptor potential motif spanning from the third to the sixth trans membrane domain. Dominant mutant alleles of Trpml3 cause hearing loss, circling behaviour, pigmentation defects and embryonic lethality in the varitint-waddler ( Va) mouse. In the inner ear these mutations cause a reduction or loss of endocochlear potentials, compound action potentials, and auditory-evoked brain stem responses. The hearing phenotype is associated with defects in the cochlea that include disorganization and fusion of stereocilia, distortions at the apical and distal regions of inner and outer hair cells, and loss of pigmented intermediate cells in the stria vascularis. In hair cells the TRPML3 protein is targeted to cytoplasmic vesicles and to the plasma membrane of stereocilia. Both the sub-cellular localization of TRPML3 and the mutant phenotype suggest that TRPML3 is critical for stereocilia bundle formation during development and may function during endocytosis or exocytosis.

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BBA - Molecular Basis of Disease (v.1772, #8)