cell-surface receptors

Receptors on cell-surfaces participate in intercellular signaling by transducing conformational change, which is induced in the receptor upon ligand-binding, into intracellular signaling and altered biophysiological activity. Thousands of receptors of varying specificity for activating ligands participate in the fine-tuned network of signaling cascades that is essential for biological functioning.

This bewildering array of receptors is variably classified according to ligand, receptor, or pathway and includes the largest protein family known (GPCRs).

Broadly, surface receptors responsive to hormones are divided into indirect-enzymatic metabotropic receptors and direct-ion channel, ionotropic receptors.

| 0 Guide-Glossary

GPCR

Guanine nucleotide-binding protein-coupled receptors, G-protein coupled receptors, GPCRs, serpentine receptors, 7TM receptors, or heptahelical receptors are a large family of protein receptors in which an intracellular G-protein is coupled to a transmembrane receptor.

▼ alpha-helices : cascade : effector enzymes : evolution : families : functions : GABA receptors : GDP/GTP : G-proteins : inorganic stimuli : opioid receptor : PDZ domains : phylogeny : physical stimuli : second messengers : stimuli : transmembrane receptors : trimeric ▼

GPCRs transduce signals from transmembrane receptors for sensory, hormonal, chemical, or photic stimuli into regulation of effector enzymes and ion channels, chemotaxis, and cellular signal transduction. GPCRs are diverse and of ancient unicellular evolutionary origin, and are found in fungi, plants, and animals. Sequence similarities of 7TM receptors, which stem from phylogenetic relatedness, are confined largely to the transmembrane domains. They share a common structure of plasma membrane-spanning helices with seven hydrophobic domains (7-TMSs). GPCRs are typically 20-28 amino acid residues long.

GPCRs are trimeric proteins that respond to a variety of specific ligands and stimuli – for example, photons, ions, biogenic amines, nucleosides, lipids, amino acids, and peptides. GPCRs are the only non-ion-channel plasma membrane receptors that are activated by inorganic chemicals and physical stimuli. Transmembrane GPCRs bind GDP when inactive, and switch the bound nucleotide to GTP when activated. Although most GPCRs do not require dimerization for their function, some receptors such as the gamma-amino butyric acid (GABA) receptors require heterodimerization of paralogs for their proper expression and function. [r]

The signalling cascade begins with attachment of a specific ligand, signaling molecule, neurotransmitter, cellular adhesion molecule, hormone, steroid, cytokine, or a specific energetic stimulus, which initiates brief (seconds) binding of GTP rather than GDP. Signal transduction is accomplished through the coupling of G-proteins, via second messengers, to various secondary pathways involving ion channels, adenylyl cyclases, and phospholipases. Further, GPCRs may also couple to other proteins, such as those containing PDZ domains. Second messengers include adenosine 3',5'-monophosphate (cAMP), cGMP, phosphoinositides, diacylglycerol (DAG), and calcium ions. Triggered events include activation of kinase cascades and phosphorylation of cytosolic factors and nuclear transcriptional factors. Activated GPCRs also recruit GPCR receptor kinases (GRKs) that phosphorylate the receptors themselves to facilitate termination of signaling or receptor turnover.

GPCR functions include:
a) generation of second messengers including cGMP and IP3, which stimulate phosphorylation reactions, causing release of second-messenger calcium ions from storage in ER,
b) generation of cAMP and activation of the transcription factor, cAMP response element binding protein (CREB) to stimulate gene transcription
c) cellular signal transduction
d) regulation of gene transcription
e) chemotaxis
f) ion channel opening (confromational change) in response to neurotransmitters

: animation G-protein : Tables Second Messengers  Cell signaling  RTKs :

It is anticipated that future elucidation of GPCR constitution will reveal alpha-helical structures, consisting of 20 to 28 amino acids each.

On-line structural representations for the human µ opioid receptor, for example, is available as a 2D schematic. The 3D structure for inactive (dark) rhodopsin has been established, and the GPCRDB server holds atomic coordinates of 3D models of GPCRs. For more detailed information on-line about GPCRs, consult the GPCR database at GPCRDB.

The GPCRs have been divided into at least six families of GPCRs showing little to no sequence similarity, which can not be traced to a single evolutionary origin.

Tables  Cell signaling  Receptor Tyrosine Kinases(RTK) :

• CELL SIGNALING ~ ERKs • GPCRs • GPCR families • hormones • Nitric Oxide• neurotransmission • neuronal interconnections ~ PKA, protein kinase A ~ PKC ~ protein kinase A ~ protein kinase C ~ protein tyrosine kinases • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs)  Cell signaling • signaling gradients • signal transduction • two-component systems • animation MAPK signal transduction : animation G-protein :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :

| 0 Guide-Glossary