G-Protein Coupled Receptors

Cross references:  Receptors in General        Ligands     Gq Protein   
Glutamate Metabotropic Receptor     GABA Metabotropic Receptor   
Serotonin Metabotropic Receptor
Acetylcholine Metabotropic Receptor   
Neuropeptide Receptor    Melatonin Receptor     Arrestin & Rhodopsin Receptors     

G protein-coupled receptor (Wiki) 
G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.

File:7TM4 (GPCR).png

The seven-transmembrane α-helix structure of a G-protein-coupled receptor.

G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates[1], and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins.
There are two principal signal transduction pathways involving the G-protein coupled receptors: the cAMP signal pathway and the Phosphatidylinositol signal pathway.

    "The human genome encodes thousands of G protein-coupled receptors ..."  and they "... are involved in a wide variety of physiological processes.   
    Some examples of their physiological roles include:
  1. the visual sense: the opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose 
  2. the sense of smell: receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
  3. behavioral and mood regulation: receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate
  4. regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response
  5. autonomic nervous system transmission: both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
  6. cell density sensing: A novel GPCR role in regulating cell density sensing.*

    Important point:
    he ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins."   '  

2015    3<73 
Functional Pairing of Class B1 Ligand-GPCR in Cephalochordate Provides Evidence of the Origin of PTH and PACAP/Glucagon Receptor Family. 
In summary, our data confirm the presence of PTH and PACAP/GLUC ligand-receptor pairs in amphioxus, demonstrating that functional homologs of vertebrate PTH and PACAP/glucagon GPCR subfamilies arose before the cephalochordate divergence from the ancestor of tunicates and vertebrates. "  

G protein (Wiki) 
"G proteins (guanine nucleotide-binding proteins) are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. [1]

G protein-coupled receptors are receptors that pass through the cell membrane. Signal molecules bind to the receptor outside the cell. The receptor inside the cell activates a G protein. The G protein activates a cascade of further compounds, and finally causes a change downstream in the cell. G protein complexes bind to phosphate groups. They function as molecular switches.

When they are attached to a complex with three phosphate groups (guanosine triphosphate [GTP]), they turn on.


When they are attached to a complex with only two phosphate groups (guanosine diphosphate [GDP]), they turn off.


Endocrinology (Kimball)

Proteins, peptides, and modified amino acids

These hydrophilic (and mostly large) hormone molecules bind to receptors on the surface of "target" cells; that is, cells able to respond to the presence of the hormone. These receptors are transmembrane proteins. Binding of the hormone to its receptor initiates a sequence of intracellular signals that may

  • alter the behavior of the cell (such as by opening or closing membrane channels) or
  • stimulate (or repress) gene expression in the nucleus by turning on (or off) the promoters and enhancers of the genes.
This is the sequence of events:
  • The hormone binds to a site on the extracellular portion of the receptor.
    • The receptors are transmembrane proteins that pass through the plasma membrane 7 times, with their N-terminal exposed at the exterior of the cell and their C-terminal projecting into the cytoplasm.
  • Binding of the hormone to the receptor
    • activates a G protein associated with the cytoplasmic C-terminal
    • This initiates the production of a "second messenger". The most common of these are
    • The second messenger, in turn, initiates a series of intracellular events (shown here as short arrows) such as
      • phosphorylation and activation of enzymes;
      • release of Ca2+ into the cytosol from stores within the endoplasmic reticulum.
    • In the case of cAMP, these enzymatic changes activate the transcription factor CREB (cAMP response element binding protein)
    • Bound to its response element
      5' TGACGTCA 3'
      in the promoters of genes that are able to respond to the hormone, activated CREB turns on gene transcription.
    • The cell begins to produce the appropriate gene products in response to the hormonal signal it had received at its surface.  

G Proteins

G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are heterotrimers (i.e., made of three different subunits) associated with
  • the inner surface of the plasma membrane and
  • transmembrane receptors of hormones, etc. These are called G protein-coupled receptors (GPCRs).
The three subunits are:
  • Gα, which carries the binding site for the nucleotide. At least 20 different kinds of Gα molecules are found in mammalian cells.

How They Work

  • In the inactive state, Gα has GDP in its binding site.
  • When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes).
  • This triggers an allosteric change in Gα causing
  • GDP to leave and be replaced by GTP.
  • GTP activates Gα causing it to dissociate from GβGγ (which remain linked as a dimer).
  • Activated Gα in turn activates an effector molecule.

    In a common example (shown here), the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP) [More].

Activated Gα is a GTPase so it quickly converts its GTP to GDP. This conversion, coupled with the return of the Gβ and Gγ subunits, restores the G protein to its inactive state. [Link to additional mechanisms that aid in turning GPCRs off.]

Some Types of Gα Subunits


This type stimulates (s = "stimulatory") adenylyl cyclase. It is the one depicted here. It is associated with the receptors for many hormones such as:

s is the target of the toxin liberated by Vibrio cholerae, the bacterium that causes cholera. Binding of cholera toxin to Gαs keeps it turned "on". The resulting continuous high levels of cAMP causes a massive loss of salts from the cells of the intestinal epithelium. Massive amounts of water follow by osmosis causing a diarrhea that can be fatal if the salts and water are not quickly replaced.


This activates phospholipase C (PLC) which generates the second messengers: q is found in G proteins coupled to receptors for


This inhibits (i = "inhibitory") adenylyl cyclase lowering the level of cAMP in the cell. Gai is activated by the receptor for somatostatin.


The "t" is for transducin, the molecule responsible for generating a signal in the rods of the retina in response to light. Gαt triggers the breakdown of cyclic GMP (cGMP).
Link to discussion of the molecular events in vision.

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7 February 2007