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“Arena3D Visualization: Human Rhodopsin receptor targets three Gα G-Proteins that belong to the Gα-t subfamily. The three G-Proteins interact with five effectors belonging to the Rhodopsin-sensitive cGMP-specific PDEases subfamily and more specifically to Phosphodiesterase 6 type of effectors.“

#transparent #diagram #receptors #rhodopsin #Arena3D #visualization #G proteins #drugs #fruits edit #sloppy editing #researchgate #2010

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)

#gpcr #gpcrs #receptors #g proteins #notes #pharmacology #biology #human biology #revision #studyblr #medblr #medicine #biomed #biomedicine #science #biochem #biochemistry #2

Alfred Goodman Gilman (born New Haven, CT, 1 July 1941 – 23 December 2015)

#alfred g. gilman #nobel prize in physiology or medicine #g proteins #g-proteins #new haven

Why do antidepressants take so long to work?

An episode of major depression can be crippling, impairing the ability to sleep, work, or eat. In severe cases, the mood disorder can lead to suicide. But the drugs available to treat depression, which can affect one in six Americans in their lifetime, can take weeks or even months to start working.

Researchers at the University of Illinois at Chicago have discovered one reason the drugs take so long to work, and their finding could help scientists develop faster-acting drugs in the future. The research was published in the Journal of Biological Chemistry.

Rasenick long suspected that the delayed drug response involved certain signaling molecules in nerve-cell membranes called G proteins.

Previous research by him and colleagues showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic AMP, which they need in order to function. The dampened signaling could be why people with depression are "numb" to their environment, Rasenick reasoned.

Samuel J. Erb, Jeffrey M. Schappi, Mark M. Rasenick. Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G protein, Gαs. Journal of Biological Chemistry, 2016; jbc.M116.727263 DOI: 10.1074/jbc.M116.727263

#G proteins #antidepressant #mental health #biology #science

In Rememberance

"The song is ended, but the melody lingers on..." - Irving Berlin. In today's blog, we will get a sneak peek into the lives of a few great scientists that we lost in 2015 and their great scientific contributions. Alfred G. Gilman, who discovered G proteins and the role of these proteins in signal transduction in cells, died on December 23rd of pancreatic cancer. He was 74. Dr. Gilman received the Nobel Prize in Physiology or Medicine in 1994 jointly with Dr. Martin Rodbell. Gilman was at the University of Virginia in 1980 when he identified and purified the first G protein from normal cells and used it to restore defective signaling in mutant leukemia cells. G-proteins were so named because they bind guanosine triphosphate (GTP) inside the cell. Gilman and Rodbell found that G-proteins act as signal transducers, which transmit and modulate signals in cells. Further studies based on his findings have explained how the body responds to its environment, how several drugs and hormones act, and how an altered function of G-proteins can lead to diseases such as cholera. When Dr. Gilman was being awarded the Nobel Prize, he said "First I activated my receptor, then my G-Protein, I was obviously extremely excited. I think I secreted all the adrenaline I had." Photo courtesy Nobelprize.org.

Leroy Stevens, who discovered pluripotent embryonic stem cells in mice, died on March 28 at age 94. He worked at the Jackson Laboratory in Bar Harbor, Maine. At the time when he joined the lab in the early 1950s, his lab had received a grant from a tobacco company and he was assigned a project to show that it wasn’t the tobacco that was injurious to health but that it was the paper in the cigarettes! For this research, when Stevens exposed his mice to the different components in the cigarettes, he observed his mice developing testicular tumors—a type of cancer known as a teratoma. Stevens found this tumor contained many different types of tissue, including hair and teeth! On further investigation of the tissue he identified similarities to cells in the mouse embryo. Then in 1970, when Stevens transplanted embryonic cells into adult mice, some of the early embryo cells gave rise to teratomas that looked and acted like spontaneous teratomas and displayed an impressive range of tissue types. Stevens called these cells from early embryos that could support differentiation "pluripotent embryonic stem cells"– leading to the origin of the term "ES cell." Photo courtesy The Jackson Laboratory.

Dr. Vernon B. Mountcastle, the neuroscientist who mapped the functional landscape of the mammalian neocortex, died early last year (January 11) at age 96. Although Dr. Mountcastle began his work in the 1940s when very little was known about the brain, he basically laid the foundations of modern neuroscience when he uncovered the mystery of higher functions like thinking and perception which are embedded in the neocortex, the thin outer layer of the brain. In the 1950s, when he was recording the activity of the neurons in the brains of cats, he recognized a pattern: those neurons that responded similarly to a stimulus like a particular type of touch, were stacked in columns, on top of one another. This led to the conclusion that the elementary pattern of organization in the cerebral cortex is a vertically oriented column or cylinder of cells working together on a single job. Dr. Mountcastle received many awards, including the prestigious Lasker in 1983 and the National Medal of Science in 1986. He was an author on more than 100 scientific papers and a book. At Johns Hopkins, Dr. Mountcastle directed the Department of Physiology from 1964 to 1980 before finishing his career as a professor of neuroscience. Vernon Mountcastle

Alexander Rich, the molecular biologist who discovered Z-DNA, the RNA-DNA double helix, and the structure of collagen, passed away on April 27 at age 90. Although the DNA molecule was first imaged using X-ray diffraction by Rosalind Franklin in 1951, before James Watson and Francis Crick published their DNA structure in 1953, they asked Dr. Rich to review their work and corroborate their ideas using X-rays. At the time, Dr. Rich was a research fellow at CalTech in the lab of Linus Pauling who received the Nobel Prize in Chemistry for his work on chemical bonds. Dr. Pauling was trying to figure out the structure of the DNA himself, as was Dr. Rich after joining his lab. However, both of them and Rosalind Franklin lost the race when Dr. Watson and Dr. Crick announced they had completed their cardboard model of the DNA five months after Dr. Rich started his work. Dr. Rich then shifted his focus to the structure of RNA. In 1956 he showed that two strands of RNA could join together to form a double helix, and in 1960, two years after he moved to M.I.T., he showed that strands of RNA and DNA could join to form a double helix. After these discoveries, Dr. Rich used X-ray crystallography to produce the first image of the RNA double helix at atomic resolution and soon after confirmed the structure of the DNA in 1973. In 1995, President Bill Clinton awarded Dr. Rich the National Medal of Science, the highest scientific honor bestowed by the federal government. Alexander Rich

Carl Djerassi, an eminent chemist who synthesized a hormone that was key to the creation of the birth control pill, died on January 30 last year at age 91. Dr. Djerassi came to the US as an Austrian Jewish refugee when he was a teenager. To be able to attend college, he wrote to Eleanor Roosevelt asking for assistance and obtained a college scholarship that would change the course of his life. Although Djerassi was often called the father of the pill, he was only one of many scientists working over decades who pioneered the chemical basis of what would become the pill. In the 1960s, the first synthetic oral contraceptive pill was developed. It was marketed by several drug companies and soon it started making major economic and social effects and impacted the lives of millions of women around the world. Carl Djerassi If you'd like to see other scientists featured in our blogs, please let us know at [email protected]. References:

Alfred G. Gilman Facts

Leroy C. Stevens, Ph.D., 1920-2015

Vernon B. Mountcastle

Alexander Rich dies at 90; MIT news

Carl Djerassi obituary ; The Guardian

Contributed by Mohar Chattopadhyay, PhD.

Regulation of proteins is needed to ensure the correct, definite, and timely activation of biological processes as you're definitely used to hearing by now. By no surprise at all, the same is true that the regulation of heterotrimeric G proteins is needed to tune signal transduction pathways in response to environmental stimuli. Mutations in the heterotrimerics, particularly Gα, are known to cause disease such as pseudohypoparathyroidism and stationary nightblindless, so studying this branch of molecular biology can give clues to treating patients with these conditions, or even designing drugs to inhibit G protein-coupled receptor (GPCR)-mediated pathways in disease-causing species.

Although the heterotrimerics are branded "G proteins", it is only the α subunit (Gα) which binds guanine nucleotides. Gα contains a Ras-like G domain with a large helical domain inserted within it. It is membrane-anchored via a post-translational myristoylation at the C-terminus. When GDP-bound, its N-terminal helix is accessible which forms extensive contacts with Gβ and Gγ subunits - together, the three form the full heterotrimeric G protein.

One helix in each Gβ and Gγ contact extensively to form a parallel coiled-coil. This makes the Gβγ complex inseparable. Gβ also has a β-propeller domain, and Gγ can be either farnesylated or geranylgeranylated at its C-terminus.

Heterotrimeric G proteins are activated upon a stimulus. Their associated GPCR detects the stimulus and transduces the signal as a conformational change. This introduces some allosteric changes onto Gα and results in a huge conformational change in the helical domain of Gα, in turn revealing the guanine nucleotide binding pocket and allowing GDP exchange for GTP. Upon binding GTP, Gα undergoes yet another conformational change and retracts its N-terminal helix, allowing it to escape from the Gβγ complex. The heterotrimeric G protein is now active.

Gβγ can be thought to act like a guanine nucleotide dissociation inhibitor (GDI) on Gα and also a subsitute for magnesium. Gα will preferentially bind GTP, but is prevented from doing so while bound to Gβγ and in the absence of a stimulus. Furthermore, Gα binds magnesium only in its GTP-bound form.

Active Gα:GTP can stimulate or repress effectors such as adenylyl cyclases, phospholipases, ion channels, and phosphatidylinositol kinases. At least in adenylyl cyclase, Gαs is stimulatory while Gαi is inhibitory. Traditionally, Gβγ was thought to not have any effect on effectors, but there is now evidence for the opposite. Gβγ can act independently of Gα (MAP kinase), synergistically (adenylyl cyclase II/IV), or antagonistically (adenylyl cyclase I).

Breaking signal transduction is just as important a step in regulation. This is done by hydrolysing GTP into GDP, and forcing Gα to complex back with Gβγ. Although Gα has an arginine finger in cis, its intrinsic hydrolysis rate is only about 100 times faster than that of the small G proteins and needs some help.

Regulators of G protein signalling (RGSs) are a type of GTPase-activating protein (GAP) which interact with all three switch regions on Gα to align water and the catalytic glutamine. The three switch regions are thought to be the reason why Gα preferentially binds GTP over GDP, and one important interaction observed is an arginine-glutamate bridge between switches II and III. This is mutated in pseudohypoparathyroidism patients.

Gα proteins may be self-regulatory, and recruit their own GAPs. Transducin (Gαt) stimulates phosphodiesterase γ (PDEγ), which has GAP activity and also recruits an RGS. Phospholipase C (PLC) has GAP activity for Gαq.

Using guanine nucleotides as a molecular switch has proven so popular in evolution that it was integrated into two discrete pathways: monomeric G proteins and heterotrimeric G proteins. Both pathways carry out signal transduction and regulate biological processes and can respond to external stimuli. Both show heavy derivatisation in far-from-canonical Ran cycling to G-domainless Gβγ signalling. What they all have in common is that the guanine nucleotide molecular switch is at the heart of their regulation for the correct, definite, and timely activation of biological processes in the response to the appropriate external stimulus.

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