TRP Channels in Disease

The mammalian TRP (transient receptor potential) family consists of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. These subfamilies encompass 28 ion channels that function as diverse cellular sensors. All of the channels are permeable to monovalent cations, and most are also permeable to Ca2+. There are strong indications that TRP channels are involved in many diseases. At this point, four channelopathies have been identified in which a defect in a TRP channel–encoding gene is the direct cause of disease. TRPs are also involved in some systemic diseases because of their role as receptors for irritants, inflammation products, and xenobiotic toxins. Other indications of the involvement of TRPs in several diseases come from correlations between the levels of channel expression and disease symptoms or from the mapping of TRP-encoding genes to susceptible chromosome regions. Finally, the phenotypes of TRP knockout mice and other transgenic models allow a degree of extrapolation to human diseases. We present an overview of current knowledge about the role of TRP channels in human disease and highlight some TRP "suspects" for which a role in disease can be anticipated. An understanding of the genetics of disease may lead to the development of targeted new therapies. The mammalian TRP (transient receptor potential) family consists of six main subfamilies that include 28 ion channels that function as cellular sensors of various phenomena, including changes in temperature, osmolarity, pH, membrane stretch, and various second messenger pathways. All of the TRP channels are permeable to monovalent cations, and most are also permeable to calcium ions. There are strong indications that TRP channels are involved in many diseases. This review highlights some TRP "suspects" for which a role in disease can be anticipated. An understanding of the genetics of disease may lead to the development of targeted new therapies.

[1]  I. Fantozzi,et al.  Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Nauli,et al.  Gating of the polycystin ion channel signaling complex in neurons and kidney cells , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  P. Thistlethwaite,et al.  Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes. , 2004, American journal of respiratory and critical care medicine.

[4]  Lin Geng,et al.  Cardiac defects and renal failure in mice with targeted mutations in Pkd2 , 2000, Nature Genetics.

[5]  B. Nilius,et al.  Mg2+-dependent Gating and Strong Inward Rectification of the Cation Channel TRPV6 , 2003, The Journal of general physiology.

[6]  F. Wolf,et al.  Magnesium in cell proliferation and differentiation. , 1999, Frontiers in bioscience : a journal and virtual library.

[7]  Jing Zhou,et al.  Polycystins and mechanosensation in renal and nodal cilia , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[8]  Craig Montell,et al.  The TRP Superfamily of Cation Channels , 2005, Science's STKE.

[9]  S. Earley,et al.  Critical Role for Transient Receptor Potential Channel TRPM4 in Myogenic Constriction of Cerebral Arteries , 2004, Circulation research.

[10]  TRPM7 Provides an Ion Channel Mechanism for Cellular Entry of Trace Metal Ions , 2003, The Journal of general physiology.

[11]  M. Freichel,et al.  TRPC4 and TRPC4-deficient mice. , 2004, Novartis Foundation symposium.

[12]  M. Pauza,et al.  Sensitization and translocation of TRPV1 by insulin and IGF-I , 2005, Molecular pain.

[13]  V. Flockerzi,et al.  Expression of CaT-like, a Novel Calcium-selective Channel, Correlates with the Malignancy of Prostate Cancer* , 2001, The Journal of Biological Chemistry.

[14]  M. Hediger,et al.  Polycystin-L is a calcium-regulated cation channel permeable to calcium ions , 1999, Nature.

[15]  K. Noben‐Trauth,et al.  Genetic Analyses of the Mouse Deafness Mutations Varitint-Waddler (Va) and Jerker (Espnje) , 2003, Journal of the Association for Research in Otolaryngology.

[16]  D. Clapham,et al.  TRP-PLIK, a Bifunctional Protein with Kinase and Ion Channel Activities , 2001, Science.

[17]  S. Bevan,et al.  Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis , 2004, The Journal of Neuroscience.

[18]  J. Nathan,et al.  Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[19]  S. Somlo,et al.  Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. , 2000, Molecular genetics and metabolism.

[20]  Functional TRPV 4 channels are expressed in human airway smooth muscle cells , 2004 .

[21]  F. Kersten,et al.  Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. , 2003, The Journal of clinical investigation.

[22]  Bernd Nilius,et al.  TRPV4 calcium entry channel: a paradigm for gating diversity. , 2004, American journal of physiology. Cell physiology.

[23]  A. Sober,et al.  Melastatin expression and prognosis in cutaneous malignant melanoma. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  N. Shimizu,et al.  LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. , 2002, Molecular cell.

[25]  J. Kinet,et al.  TRPM4 Regulates Calcium Oscillations After T Cell Activation , 2004, Science.

[26]  C. Johnson,et al.  Regulation of Vertebrate Cellular Mg2+ Homeostasis by TRPM7 , 2003, Cell.

[27]  D. Clapham,et al.  TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function , 2005, Nature Genetics.

[28]  S. Simon,et al.  A possible role for TRPV4 receptors in asthma. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[29]  M. Passos-Bueno,et al.  A gene which causes severe ocular alterations and occipital encephalocele (Knobloch syndrome) is mapped to 21q22.3. , 1996, Human molecular genetics.

[30]  Peter McIntyre,et al.  ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures , 2003, Cell.

[31]  K. Bölcskei,et al.  Role of Transient Receptor Potential Vanilloid 1 Receptors in Adjuvant-Induced Chronic Arthritis: In Vivo Study Using Gene-Deficient Mice , 2005, Journal of Pharmacology and Experimental Therapeutics.

[32]  M. Hediger,et al.  Calcium-Selective Ion Channel, CaT1, Is Apically Localized in Gastrointestinal Tract Epithelia and Is Aberrantly Expressed in Human Malignancies , 2002, Laboratory Investigation.

[33]  V. Sheffield,et al.  Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia , 2002, Nature Genetics.

[34]  E. Brown,et al.  Identification and characterization of the single channel function of human mucolipin‐1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway , 2002, FEBS letters.

[35]  J. Molkentin,et al.  Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. , 2004, Biochemical and biophysical research communications.

[36]  K. Johnson.  An Update. , 1984, Journal of food protection.

[37]  P. Geppetti,et al.  Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function , 2004, British journal of pharmacology.

[38]  M. Biel,et al.  Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4−/− mice , 2001, Nature Cell Biology.

[39]  B. Dworniczak,et al.  The Ion Channel Polycystin-2 Is Required for Left-Right Axis Determination in Mice , 2002, Current Biology.

[40]  Yuji Arai,et al.  A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor–regulated channel , 2003, The Journal of cell biology.

[41]  D. McKemy,et al.  Molecular Pain BioMed Central Review , 2005 .

[42]  G. Bach.  Mucolipidosis type IV. , 2001, Molecular genetics and metabolism.

[43]  P. Anand,et al.  Increased vanilloid receptor VR1 innervation in vulvodynia , 2004, European journal of pain.

[44]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[45]  T. Gudermann,et al.  A critical role of TRPM channel‐kinase for human magnesium transport , 2005, The Journal of physiology.

[46]  Bernd Nilius,et al.  The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels , 2004, Nature.

[47]  M. Freichel,et al.  Impairment of Store-Operated Ca2+ Entry in TRPC4−/− Mice Interferes With Increase in Lung Microvascular Permeability , 2002, Circulation research.

[48]  K. Steel.  Varitint-waddler: A double whammy for hearing , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Shujian Wu,et al.  Expression and Characterization of Human Transient Receptor Potential Melastatin 3 (hTRPM3)* , 2003, Journal of Biological Chemistry.

[50]  M. Nelson,et al.  Transient Receptor Potential Channels Regulate Myogenic Tone of Resistance Arteries , 2002, Circulation research.

[51]  J. Westwick,et al.  Transient receptor potential (TRP) channels as potential drug targets in respiratory disease. , 2003, Cell calcium.

[52]  M. Nadler,et al.  LTRPC7 is a Mg·ATP-regulated divalent cation channel required for cell viability , 2001, Nature.

[53]  P. Anand,et al.  Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin. , 2005, Urology.

[54]  A. Patapoutian,et al.  ThermoTRP channels and beyond: mechanisms of temperature sensation , 2003, Nature Reviews Neuroscience.

[55]  J. Friedman,et al.  Abnormal osmotic regulation in trpv4-/- mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Levine,et al.  Hypotonicity Induces TRPV4-Mediated Nociception in Rat , 2003, Neuron.

[57]  K. Chung,et al.  Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. , 2004, American journal of respiratory and critical care medicine.

[58]  M. Valverde,et al.  Swelling-activated Ca2+ Entry via TRPV4 Channel Is Defective in Cystic Fibrosis Airway Epithelia* , 2004, Journal of Biological Chemistry.

[59]  J. Kennedy,et al.  Altered TRPC7 gene expression in bipolar-I disorder , 2001, Biological Psychiatry.

[60]  P. Anand,et al.  Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain , 2005, BMC women's health.

[61]  P. Thistlethwaite,et al.  Role of capacitative Ca2+ entry in bronchial contraction and remodeling. , 2002, Journal of applied physiology.

[62]  J. Putney,et al.  The mammalian TRPC cation channels. , 2004, Biochimica et biophysica acta.

[63]  R. Egan,et al.  Functional TRPV4 channels are expressed in human airway smooth muscle cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[64]  J. Pelletier,et al.  Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression. , 2000, Human molecular genetics.

[65]  M. Pericak-Vance,et al.  A Mutation in the TRPC6 Cation Channel Causes Familial Focal Segmental Glomerulosclerosis , 2005, Science.

[66]  A. Hudspeth,et al.  Vanilloid Receptor–Related Osmotically Activated Channel (VR-OAC), a Candidate Vertebrate Osmoreceptor , 2000, Cell.

[67]  Craig Montell,et al.  A unified nomenclature for the superfamily of TRP cation channels. , 2002, Molecular cell.

[68]  G. Germino,et al.  Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents , 2000, Nature.

[69]  M. Kanzaki,et al.  Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I , 1999, Nature Cell Biology.

[70]  J. Levine,et al.  Cellular/molecular Transient Receptor Potential Vanilloid 4 Is Essential in Chemotherapy-induced Neuropathic Pain in the Rat , 2004 .

[71]  D. Julius,et al.  The vanilloid receptor: a molecular gateway to the pain pathway. , 2001, Annual review of neuroscience.

[72]  Ying Yu,et al.  Inhibition of endogenous TRP1 decreases capacitative Ca2+ entry and attenuates pulmonary artery smooth muscle cell proliferation. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[73]  Heidi L. Rehm,et al.  TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells , 2004, Nature.

[74]  N. Shimizu,et al.  Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. , 1998, Genomics.

[75]  A. Minassi,et al.  Development of the First Ultra-Potent “Capsaicinoid” Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential , 2005, Journal of Pharmacology and Experimental Therapeutics.

[76]  J. Macdonald,et al.  A Key Role for TRPM7 Channels in Anoxic Neuronal Death , 2003, Cell.

[77]  M. Shapero,et al.  Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. , 2001, Cancer research.

[78]  M. Caterina,et al.  Altered Thermal Selection Behavior in Mice Lacking Transient Receptor Potential Vanilloid 4 , 2005, The Journal of Neuroscience.

[79]  M. Tymianski,et al.  TRPM7 and Ischemic CNS Injury , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[80]  De-Pei Li,et al.  Cardiac vanilloid receptor 1‐expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats , 2003, The Journal of physiology.

[81]  S. Simon,et al.  Vanilloid receptor activation by 2- and 10-microm particles induces responses leading to apoptosis in human airway epithelial cells. , 2003, Toxicology and applied pharmacology.

[82]  T. Gudermann,et al.  Insights into the molecular nature of magnesium homeostasis. , 2004, American journal of physiology. Renal physiology.

[83]  T. Vogt,et al.  Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  P. Anand,et al.  Vanilloid receptor 1 immunoreactivity in inflamed human bowel , 2001, The Lancet.

[85]  Akash A. Patel,et al.  Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[86]  A. Kurosky,et al.  TRPC1 forms the stretch-activated cation channel in vertebrate cells , 2005, Nature Cell Biology.

[87]  J. Westwick,et al.  TRP channels as drug targets. , 2004, Novartis Foundation symposium.

[88]  H. Pan,et al.  Sensing Tissue Ischemia: Another New Function for Capsaicin Receptors? , 2004, Circulation.

[89]  P. Delmas,et al.  Polycystins, calcium signaling, and human diseases. , 2004, Biochemical and biophysical research communications.

[90]  E. Haddad,et al.  Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family , 2002, Nature Genetics.

[91]  E. Brown,et al.  CaT1 expression correlates with tumor grade in prostate cancer. , 2001, Biochemical and biophysical research communications.

[92]  Veit Flockerzi,et al.  Alternative Splicing Switches the Divalent Cation Selectivity of TRPM3 Channels* , 2005, Journal of Biological Chemistry.

[93]  Brigitte L. Arduini,et al.  Defective Skeletogenesis with Kidney Stone Formation in Dwarf Zebrafish Mutant for trpm7 , 2005, Current Biology.

[94]  S. Somlo,et al.  The pathogenesis of autosomal dominant polycystic kidney disease: an update. , 2000, Current opinion in nephrology and hypertension.

[95]  M. I. Lomax,et al.  DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24. , 2001, American journal of human genetics.

[96]  P. Delmas.  Polycystins From Mechanosensation to Gene Regulation , 2004, Cell.

[97]  P. McIntyre,et al.  A TRP Channel that Senses Cold Stimuli and Menthol , 2002, Cell.

[98]  J A Peters,et al.  Guide to receptors and channels, 1st edition. , 2004, British journal of pharmacology.

[99]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[100]  Bernd Nilius,et al.  TRP channels: a TR(I)P through a world of multifunctional cation channels , 2005, Pflügers Archiv.

[101]  J. Satoh,et al.  Warm Temperature-sensitive Transient Receptor Potential Vanilloid 4 (TRPV4) Plays an Essential Role in Thermal Hyperalgesia* , 2004, Journal of Biological Chemistry.

[102]  V. Flockerzi,et al.  TRPV6 and prostate cancer: cancer growth beyond the prostate correlates with increased TRPV6 Ca2+ channel expression. , 2004, Biochemical and biophysical research communications.

[103]  P. Anand,et al.  Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus , 2004, European journal of gastroenterology & hepatology.

[104]  S. Weremowicz,et al.  Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects* , 1998, The Journal of Biological Chemistry.

[105]  Shujian Wu,et al.  Expression and Characterization of Human Transient Receptor Potential Melastatin 3 (hTRPM3)* , 2003, Journal of Biological Chemistry.

[106]  G. Barritt,et al.  Evidence that TRPM8 Is an Androgen-Dependent Ca2+ Channel Required for the Survival of Prostate Cancer Cells , 2004, Cancer Research.

[107]  P. Anand,et al.  Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency , 2003, The Lancet.

[108]  S. Simon,et al.  TRPV1 receptors mediate particulate matter-induced apoptosis. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[109]  E. Brown,et al.  Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV. , 2004, Biochemical and biophysical research communications.

[110]  Gary R Lewin,et al.  Mechanosensation and pain. , 2004, Journal of neurobiology.

[111]  D. Clapham,et al.  Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization , 2004, The Journal of Neuroscience.

[112]  C. Montell,et al.  The TRP Channels, a Remarkably Functional Family , 2002, Cell.

[113]  Jing Zhou,et al.  The human polycystic kidney disease 2-like (PKDL) gene: exon/intron structure and evidence for a novel splicing mechanism , 2000, Mammalian Genome.

[114]  M. Tominaga,et al.  Thermosensation and pain. , 2004, Journal of neurobiology.