TRPC is a family of

transient receptor potential Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TR ...

cation channels in animals. TRPC channels form the subfamily of channels in humans most closely related to

drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

TRP channels. Structurally, members of this family possess a number of similar characteristics, including 3 or 4

ankyrin Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral mem ...

repeats near the N-terminus and a TRP box motif containing the invariant EWKFAR sequence at the proximal C-terminus. These channels are non-selectively permeable to cations, with a prevalence of calcium over sodium variable among the different members. Many of TRPC channel subunits are able to coassemble. The predominant TRPC channels in the mammalian

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

are the TRPC 1,4 and 5 and they are densely expressed in corticolimbic brain regions, like the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...

and lateral septum. These 3 channels are activated by the

metabotropic glutamate receptor 1 The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and ...

agonist

dihydroxyphenylglycine (''S'')-3,5-Dihydroxyphenylglycine or DHPG is a potent agonist of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5. DHPG was the first agonist shown to be selective for group I mGluRs. Agonist activity is found in only the ( ...

. In general, TRPC channels can be activated by phospholipase C stimulation, with some members also activated by

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...

. There is at least one report that TRPC1 is also activated by stretching of the membrane and TRPC5 channels are activated by extracellular reduced

thioredoxin Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by ''TXN'' and '' TXN2'' genes. Loss-of-fu ...

. It has long been proposed that TRPC channels underlie the

calcium release activated channel Calcium release-activated channels (CRAC) are specialized plasma membrane Ca2+ ion channels. When calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that f ...

s observed in many cell types. These channels open due to the depletion of intracellular calcium stores. Two other proteins, stromal interaction molecules (STIMs) and Orais, however, have more recently been implicated in this process.

STIM1 Stromal interaction molecule 1 is a protein that in humans is encoded by the ''STIM1'' gene. STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane. Even though the pro ...

and

TRPC1 Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the ''TRPC1'' gene. Function TRPC1 is an ion channel located on the plasma membrane of numerous human and animal cell types. It is a nonspecific cation ...

can coassemble, complicating the understanding of this phenomenon. TRPC6 has been implicated in late onset Alzheimer's disease.

Role in cardiomyopathies

Research on the role of TRPC channels in

cardiomyopathies Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

is still in progress. An upregulation of

TRPC3 Short transient receptor potential channel 3 (TrpC3) also known as transient receptor protein 3 (TRP-3) is a protein that in humans is encoded by the TRPC3 gene. The TRPC3/6/7 subfamily are implicated in the regulation of vascular tone, cell growt ...

, and

TRPC6 Transient receptor potential cation channel, subfamily C, member 6, also known as TRPC6, is a human gene encoding a protein of the same name. TRPC6 is a transient receptor potential channel of the classical TRPC subfamily. It has been associated ...

genes are seen in heart disease states including fibroblast formation and cardiovascular disease. The TRPC channels are suspected of responding to an overload of hormonal and mechanical stimulation in cardiovascular disease, contributing to pathological remodelling of the heart. TRPC1 channels are activated by receptors coupled to phospholipase C (PLC), mechanical stimulation, and depletion of intracellular calcium stores. TRPC1 channels are found on

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

, smooth muscle, and

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

. Upon stimulation of these channels in cardiovascular disease, there is an increase in hypertension and cardiac

hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...

. TRPC1 channels mediate smooth muscle proliferation in the presence of pathological stimuli which contributes to hypertension. Mice with myocardial hypertrophy exhibit increased expression of TRPC1. The deletion of the TRPC1 gene in these mice resulted in reduced hypertrophy upon stimulation with hypertrophic stimuli, inferring that TRPC1 has a role in the progression of cardiac hypertrophy. TRPC3 and TRPC6 channels are activated by PLC stimulation and

(DAG) production. Both these TRPC channel types play a role in cardiac hypertrophy and vascular disease like TRPC1. In addition, TRPC3 is upregulated in the atria of patients with atrial fibrillation (AF). TRPC3 regulates angiotensin II-induced cardiac hypertrophy which contributes to the formation of

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

. Accumulation of fibroblasts in the heart can manifest into AF. Experiments blocking TRPC3 show a decrease in fibroblast formation and reduced AF susceptibility. TRPC1, TRPC3, and TRPC6 channels are all involved in cardiac hypertrophy. The mechanism of how TRPC channels promote cardiac hypertrophy is through activation of the

calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be block ...

pathway and the downstream transcription factor nuclear factor of activated T-cells (NFAT). Pathological stress or hypertrophic agonists will trigger

G-protein coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...

(GPCRs) and activates PLC to form DAG and

inositol triphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...

(IP3). IP3 promotes the release of internal calcium stores and the influx of calcium via TRPC. When intracellular calcium reaches a threshold, it will activate the calcineurin /NFAT pathway. DAG activates the calcineurin/NFAT pathway directly. NFAT translocate into the nucleus and induce gene transcription of more TRPC genes. This creates a

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in th ...

loop, leading to a state of hypertrophic gene expression and thus, cardiac growth and remodelling of the heart. TRPC channel's involvement in well studied signaling pathways and significance in gene impact on human diseases make it a potential target for

drug therapy Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term ''medical ther ...

. TRPC has been shown to potentiate inhibition in the olfactory bulb circuit, providing a mechanism for improving olfactory abilities.

Genes

TRPC2 Transient receptor potential cation channel, subfamily C, member 2, also known as TRPC2, is a protein that in humans is encoded by the ''TRPC2'' pseudogene. This protein is not expressed in humans but is in certain other species such as mouse. ...

, TRPC4,

TRPC5 Short transient receptor potential channel 5 (TrpC5) also known as transient receptor protein 5 (TRP-5) is a protein that in humans is encoded by the ''TRPC5'' gene. TrpC5 is subtype of the TRPC family of mammalian transient receptor potential io ...

TRPC7 Transient receptor potential cation channel, subfamily C, member 7, also known as TRPC7, is a human gene encoding a protein of the same name. See also * TRPC TRPC is a family of transient receptor potential cation channels in animals. TRPC ch ...

References

External links

* * * {{DEFAULTSORT:Trpc Membrane proteins Ion channels