#gpcrs

[biomedicool]

GPCRs/7-transmembrane receptors (7TM receptors)

G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes. 

Structure

single polypeptide chain comprising of seven transmembrane α-helices

extracellular N-terminal domain of varying length, 

intracellular C-terminal domain.

length of the extracellular N terminus and the location of the agonist binding domain determines family.

The long, third cytoplasmic loop couples to the G-protein 

Usually particular receptor subtypes couple selectively with particular G-proteins

For small molecules, such as noradrenaline, the ligand-binding domain of class A receptors is buried in the cleft between the α-helical segments within the membrane. Peptide ligands bind more superficially to the extracellular loops

G protein system

GPCRs interact with G proteins in the plasma membrane when an external signaling molecule binds to a GPCR, causes a conformational change in the GPCR.  G-proteins comprise a family of membrane-resident proteins whose function is to recognise activated GPCRs and pass on the message to the effector systems that generate a cellular response. 

G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). 

The G proteins that associate with GPCRs are heterotrimeric, (alpha beta and gamma subunits)

 alpha and gamma are attached to the plasma membrane by lipid anchors 

Trimer in resting state 

activated alpha monomer and beta/gamma dimer

Guanine nucleotides bind to the α subunit, which has enzymic activity, catalysing the conversion of GTP to GDP. The β and γ subunits remain together as a βγ complex. All three subunits are anchored to the membrane through a fatty acid chain, coupled to the G-protein through a reaction known as prenylation.

G-proteins are freely diffusible so a single pool of G-protein in a cell can interact with several different receptors and effectors 

When GPCR is activated by an agonist, a conformational change causes it to acquire high affinity for αβγ (G protein)

bound GDP dissociates and is replaced with GTP, which in turn causes dissociation of the G-protein trimer, releasing α-GTP and βγ subunits - the ‘active’ forms of the G-protein

which diffuse in the membrane and can associate with various enzymes and ion channels

Signalling is terminated on hydrolysis of GTP to GDP through the GTPase activity of the α subunit.

resulting α–GDP dissociates from the effector, and reunites with βγ

Attachment of the α subunit to an effector molecule increases its GTPase activity

GTP hydrolysis is termination --> activation of the effector tends to be self-limiting

Second messenger targets for G proteins

Main targets:

Adenylyl cyclase (responsible for cAMP formation)

Phospholipase C (inositol phosphate and diacylglycerol (DAG) formation)

Ion channels, particularly calcium and potassium channels

Rho A/Rho kinase (system controlling the activity of many signalling pathways for cell growth and proliferation, smooth muscle contraction, etc.)

Mitogen-activated protein kinase (MAP kinase) system controlling cell functions eg division.

(notes on these coming soon)

[faultfalha]

Superluminal, a startup that harnesses the power of quantum mechanics to develop treatments for cancer and other diseases, has announced that it has secured investment from RA Capital Management and Nvidia. The company is focused on discovering and developing drugs that target GPCRs, a class of proteins that are involved in almost every major biochemical process in the body.

[rahuldesai9123]

Frontier Pharma: Type 2 Diabetes Mellitus-Therapies Targeting GPCRs and Protein Kinases Dominate Pipeline, with Strong Repositioning Opportunities into Associated Areas, Including Obesity and Cardiovascular Disease

[larryhbernsteinme]

Dark Cellular Receptors

Dark Cellular Receptors

Larry H. Bernstein, MD, FCAP, Curator

LPBI

  Nov 10, 2015   GEN News Highlights

Unraveling the Mysteries of “Dark” Cellular Receptors   

http://www.genengnews.com/gen-news-highlights/unraveling-the-mysteries-of-dark-cellular-receptors/81251956/

  A research team from the University of North Carolina School of Medicine (UNC) and University of California, San Francisco…

View On WordPress

[zebraphys]

Chemogenetics have dramatically transformed how  biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings

Here we highlight a specific chemogenetic application that extends the utility of the concept ofRASSLs (receptors activated solely by synthetic ligands)

 DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. 

[cresset-group]

March 2014 Newsletter

http://www.cresset-group.com/2014/03/march-2014-newsletter/

[aboutthebrain]

How the Body's Energy Molecule Transmits Three Types of Taste to the Brain

PHILADELPHIA — Saying that the sense of taste is complicated is an understatement, that it is little understood, even more so. Exactly how cells transmit taste information to the brain for three out of the five primary taste types was pretty much a mystery, until now.

Taste buds in a circumvallate papilla in a mouse tongue with types I, II and III taste cells visualized by cell-type-specific fluorescent antibodies. Type II cells respond to sweet, bitter, and umami tastes by signaling to the central nervous system by non-vesicular ATP release. Taruno and colleagues have identified CALHM1 as a voltage-gated ATP release channel that mediates this response to these taste modalities.

A team of investigators from nine institutions discovered how ATP – the body’s main fuel source – is released as the neurotransmitter from sweet, bitter, and umami, or savory, taste bud cells. The CALHM1 channel protein, which spans a taste bud cell’s outer membrane to allow ions and molecules in and out, releases ATP to make a neural taste connection. The other two taste types, sour and salt, use different mechanisms to send taste information to the brain.

Kevin Foskett, PhD, professor of Physiology at the Perelman School of Medicine, University of Pennsylvania, and colleagues from the Monell Chemical Senses Center, the Feinstein Institute for Medical Research, and others, describe in Nature how ATP release is key to this sensory information path. They found that the calcium homeostasis modulator 1 (CALHM1) protein, recently identified by the Foskett lab as a novel ion channel, is indispensable for taste via release of ATP.  

“This is an example of a bona fide ATP ion channel with a clear physiological function,” says Foskett. “Now we can connect the molecular dots of sweet and other tastes to the brain.”

Taste buds have specialized cells that express G-protein coupled receptors (GPCRs) that bind to taste molecules and initiate a complex chain of molecular events, the final step of which Foskett and collaborators show is the opening of a pore in the cell membrane formed by CALHM1. ATP molecules leave the cell through this pore to alert nearby neurons to continue the signal to the taste centers of the brain. CALHM1 is expressed specifically in sweet, bitter, and umami taste bud cells.

Mice in which CALHM1 proteins are absent, developed by Feinstein’s Philippe Marambaud, PhD, have severely impaired perceptions of sweet, bitter and umami compounds; whereas, their recognition of sour and salty tastes remains mostly normal. The CALHM1 deficiency affects taste perception without interfering with taste cell development or overall function.

Using the CALHM1 knockout mice, team members from Monell and Feinstein tested how their taste was affected. “The mice are very unusual,” says Monell’s Michael Tordoff, PhD. “Control mice, like humans, lick avidly for sucrose and other sweeteners, and avoid bitter compounds. However, the mice without CALHM1 treat sweeteners and bitter compounds as if they were water. They can’t taste them at all.”

From all lines of evidence, the team concluded that CALHM1 is an ATP-release channel required for sweet, bitter, and umami taste perception. In addition, they found that CALHM1 was also required for  “nontraditional” Polycose, calcium, and aversive high-salt tastes, implying that the deficit displayed in the knockout animals might best be considered as a loss of all GPCR-mediated taste signals rather than simply sweet, bitter and umami taste.

Interestingly, CALHM1 was originally implicated in Alzheimer’s disease, although the link is now less clear. In 2008, co-author Marambaud identified CALHM1 as a risk gene for Alzheimer’s. They discovered that a CALHM1 genetic variant was more common among people with Alzheimer’s and they went on to show that it leads to a partial loss of function. They also found that this novel ion channel is strongly expressed in the hippoca

mpus, a brain region necessary for learning and memory. So far, there is no connection between taste perception and Alzheimer’s risk, but Marambaud suspects that scientists will start testing this hypothesis. Source:http://www.sciencedaily.com/releases/2013/03/130306134354.htm