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TRP Ion Channel Family

Discovery and general properties

Transient receptor potential (TRP) genes were first described in the fruit fly Drosophila melanogaster. Studies in its visual system identified a visually impaired mutant fly that had a transient response to steady light instead of the sustained electro-retinogram recorded in the wild type. This is mutant was therefore called transient receptor potential. However, it took about two decades before the trp gene was identified in 1989. From its structural resemblance to other cation channels and detailed analysis of the permeation properties of the light-induced current in the trp mutant fly, the product of the trp gene was proposed to be a six-transmembrane-segment protein which functions as a Ca2+-permeable cation channel.

Based on their domain structure and details of their sequences, members of the TRP channel family can be divided into seven subfamilies: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Currently, over 100 TRP genes have been identified in various animals. TRP genes of human are diverse in length and range between 11.4 and about 911 kb, with the number of exons varying from 11 to 39. The overall protein sequence homology between subfamily members in the same species is usually about 35%, but for clear duplication pairs (such as TRPC6 and TRPC7, TRPM4 and TRPM5, and TRPV5 and TRPV6) this may reach 50 to 80%.

Figure 1. A phylogenetic tree of human TRP channels.

Functional TRP channels are composed of homomeric or heteromeric tetramers of subunits from these subfamilies. A common structural feature of the TRP channel subunits is a core of six transmembrane domains (S1-S6), flanked by intracellular amino- and carboxyl-termini. There is a complex pore-loop structure between S5 and S6, which breaches the extracellular plane of the plasma membrane and forms the ion selectivity filter. This overall architecture resembles that of the voltage-gated and cyclic nucleotide-gated channel families. The TRPC, TRPM, TRPV, TRPA, and TRPN subfamilies, referred to as Group I TRP channels, resemble one another more closely than they do the TRPP or TRPML subfamilies, which are classified as Group II (Figure 2).

Figure 2. TRP superfamily of cation channels.

Localization and function

TRPs are expressed in almost every cell type in both excitable and non-excitable tissues. TRP channels are present in all cellular membranes, with the exception of the nuclear envelope and mitochondria. Most TRP channels are localized in the plasma membrane, where they have an essential role in the influx and/or transcellular machinery that transports Mg2+, Ca2+and trace metal ions, and they modulate the driving force for ion entry. These contributions are essential for several physiological processes, ranging from pure sensory functions and homeostatic functions to many other motile functions, such as muscle contraction and vasomotor control.

• TRPC subfamily

Channel subunitPhysiological functions
TRPC1Generation of the excitatory postsynaptic potential in brain; netrin-1 and brain-derived neurotrophic factor (BDNF)-mediated growth cone guidance; alertness and appetite; connections to sleep/wakefulness states, brain development; glutamate signaling in hippocampus
TRPC2Pheromone detection that regulates sexual and social behaviors, such as gender recognition and male-male aggression (mouse)
TRPC3BDNF-mediated growth cone guidance (TRPC1-independent); spine formation in brain; γ-aminobutyric acid signaling in striatum; astrocyte function; cerebral vaso-motor control; moto-control in cerebellum; erythropoietin function; functional coupling to orexin receptor
TRPC4Endothelium-dependent vasorelaxation and regulation of transcellular permeation of the endothelial layer; cell-cell adhesion in endothelium through junctional proteins
TRPC5Brain development (together with TRPC1); anxiety, fear and reward processing in nucleus accumbens; neurite growth, growth cone guidance and morphology
TRPC6Vaso-motor regulation; α1 signaling in smooth muscle; smooth muscle proliferation; angiogenesis; promotion of dendrite growth and synapse forming in the developing brain; endocannabinoid signaling in the brain; glomerular filter integrity in the kidney
TRPC7Controls respiratory rhythm activity in pre-Bötzinger complex in the brain

• TRPV subfamily

Channel subunitPhysiological functions
TRPV1Thermo-sensation (heat); autonomic thermoregulation; synaptic plasticity in the brain (long-term depression); pain management; endocannabinoid signaling in the brain; nociception; food intake regulation; growth cone guidance in the brain
TRPV2Thermo-sensation (noxious heat); axon outgrowth in spinal motor neurons; nociception; critical for phagocytosis in macrophages
TRPV3Thermo-sensation (moderate heat); skin integrity; nociception; wound healing, hair growth and sebocyte function
TRPV4Thermo-sensation (moderate heat); mechano-sensation; osmo-sensation; nociception; modulation of cell migration; mechano-receptor in urothelium; endothelium vaso-motor control and possible shear stress sensor; osteogenesis and osteoclast function; important in human bone and neurodegenerative diseases
TRPV5Ca2+ (re)absorption channel in kidney and intestines
TRPV6Ca2+ (re)absorption channel in intestines and kidney; key player in Ca2+/1,25-dihydroxyvitamin D3-induced keratinocyte development in the skin

• TRPM subfamily

Channel subunitPhysiological functions
TRPM1Light response in ON bipolar retinal ganglia cells; tumor repressor in melanoma cells
TRPM2Oxidative and nitrosative stress response; pancreas insulin release; activation of granulocytes; critical in apoptosis
TRPM3Steroid hormone (pregnanolon) sensor; possible regulator in endocrine pancreas, glia cells and cerebellar Purkinje cells
TRPM4Mast cell degranulation (histamine release) and migration as a critical Ca-impermeable cation channel regulating Ca2+ entry; vasopressin release from paraventricular and supraoptic hypothalamic nuclei; catecholamine release from chromaffin cells;
TRPM5Taste (sweet, bitter, umami); trigeminal nasal chemoreception; positive regulator of glucose-induced insulin release
TRPM6Mg2+ homeostasis and reabsorption in kidney and intestine
TRPM7Mg2+ homeostasis and reabsorption in kidney and intestine; gastrulation; cell cycle control; development of thymocytes (thymopoiesis); cell migration
TRPM8Thermo-sensation (cold); sperm motility, acrosome reaction

• TRPA subfamily

Channel subunitPhysiological functions
TRPA1Thermo-sensation (noxious cold); the most versatile chemo-sensor; olfactory responses; nociception; cold-induced contraction in colon and bladder

• TRPA subfamily

Channel subunitPhysiological functions
TRPML1Essential for endocytosis and endosomal/lysosomal function; regulation of autophagy
TRPML2Endosomal/lysosomal function
TRPML3Endosomal/lysosomal function; autophagy

• TRPP subfamily

Channel subunitPhysiological functions
TRPP2Cardiac, skeletal and renal development; negative regulator of endogenous mechano-sensitive channels; mechano-receptor and flow-sensor in endothelium; integrity of the vessel wall; apoptosis
TRPP3Renal development; part of putative sour sensor

TRP channels and disease

Several TRP genes are implicated in a wide range of diseases in humans. These fall under the umbrella of the ‘channelopathies’, which are defined as diseases caused by impaired channel functions, resulting from either mutations in the encoding gene or an acquired mechanism, such as autoimmunity.

 ChannelDiseases
Loss-of-function (LOF) mutationsTRPM1Stationary night blindness
TRPM2Amyotrophic lateral sclerosis and parkinsonism-dementia
TRPM6Hypomagnesemia and hypocalcemia
TRPP2Kidney disease (ADPKD)
TRPML1Childhood neurodegenerative disease (MLIV)
Gain-of-function (GOF) mutationsTRPC6Kidney disease (FSGS)
TRPV4Skeletal disease (brachyolmia, metatropic dysplasia, SMDK); neuropathies (SMA, CMT2C)
TRPM4Progressive familial heart block type I
TRPA1Familial episodic pain syndrome

The discovery of TRP channels has revolutionized the understanding of many sensory and general physiological processes. TRPs usually act in concert with other ion channels and proteins. In many cases, these mechanisms are evolutionarily conserved from invertebrates to humans. It is not surprising that inherited impairments of TRP channel functions lead to disease. In addition, changes in channel expression levels or channel sensitization or desensitization, resulting in exaggerated or diminished responses to diverse pathological stimuli, can also contribute to the pathophysiology of TRP-related diseases. Diverse endogenous agents released during early disease stages can also influence TRP channel functions and lead to inflammation and the progression of the disease. These findings spotlight TRP channels as important pharmacological targets. Therefore, further understanding of the physiological roles and activation mechanisms of these channels may provide novel insights into the etiology and possible treatments of many TRP-related diseases.

References:

  1. Michael J. Caterina. Chapter 1–An Introduction to Transient Receptor Potential Ion Channels and Their Roles in Disease. TRP Channels As Therapeutic Targets. 2015:1-12.
  2. Song MY, Yuan JX. Introduction to TRP channels: structure, function, and regulation. Advances in experimental medicine and biology. 2010, 661:99.
  3. Craig Montell. The history of TRP channels, a commentary and reflection. Pflügers Archiv - European Journal of Physiology. 2011, 461(5):499-506.
  4. Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biology, 2011, 12(3):218.
  5. Li Z, et al. Recessive Mutations of the Gene TRPM1, Abrogate ON Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans. American Journal of Human Genetics. 2009, 85(5):711.
  6. Vennekens R. Emerging concepts for the role of TRP channels in the cardiovascular system. Journal of Physiology. 2011, 589(7):1527–1534.
For research use only. Not intended for any clinical use.

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