74. Membrane receptor signaling Flashcards
IC and membrane receptors
- Lipophilic hormones can easily pass the cellular membrane and bind to cytoplasmic proteins (receptors). Reaching the nucleus, they exert their biological actions through the modification of genetic expression of certain proteins.
- Water soluble (hydrophilic) peptides and glycoprotein hormones exert their actions by binding to membrane surface receptors.
- In many cases, the EC receptor transmembrane protein is also an ion channel. In other cases, the receptor is a separate protein of the cell membrane or the cytoplasm.
Transduction is independent of G-protein
- In some cases, the receptor is a special transmembrane protein. With a ligand binding part located on the outer side, a central part which reaches through the membrane, and an inner part, where the same protein continues in a section exhibiting phosphorylase activity.
- If a ligand bond is formed on the outer surface, the intracellular polypeptide chain phosphorylates and activates the receptor itself or other cellular proteins, leading to biological action.
Transduction is G protein dependent
- After the formation of a receptor - ligand complex, the activation of the G protein (an intracellular membrane protein) is necessary to initiate the transduction.
- The name G protein refers to the fact that the activated protein binds GTP so it is able to either activate or inactivate various structures of the cellular membrane.
- The activated G protein may migrate to a remote ion channel protein, where it activates (Gs effect) or inactivates (Gi effect) these channels.
- The activated G protein may activate several enzymes bond to the IC side of the membrane, which elicit a wide range of biological effects through various transduction mechanisms.
The receptor is also an ion channel
- Some receptors serve as an ion channel; the ligand binding site is on the EC side.
- Nicotinic acetylcholine receptor (n-ACh-R) is a typical member of the ion channel forming transmembrane proteins, which can be found in both the central and peripheral nervous systems.
- The ion channel is in “closed state” before ACh binds to this receptor. After the binding of ACh, a conformational change takes place, which opens a cation channel (“open state”), significantly enhancing the flow of cations (usually sodium ions) into the cell.
- After a certain time, the open channel becomes inactivated. The ligand bond still exists, but the change of the conformation does not allow any cation flow: an “inactivated” channel is yielded. After the dissociation of the ligand, the channel closes again.
Anion-receptors
In the most important inhibitory synapses of the central nervous system the necessary hyperpolarization is caused by the opening of anion channels.
Anion chanels are not specific, mainly the influx chloride, but also that of hydrogen carbonate causes the hyperpolarization.
Two major mediators are known:
– GABA (gamma-amino-butyricacid)
– glycine
GABA acts on two receptors (GABA-A or GABA-B), the former is ionotropic, the latter is metabotropic. Activation of GABA-B decreases IC cAMP levels and, besides this, (in a G protein mediated way) it has an effect also on ion (potassium) channels.
G protein mechanism
- G proteins are protein molecules located intracellularly and consist of three subunits.
- By default alpha subunit binds a GDP and forms a complex with beta and gamma subunits.
- G proteins are connected to receptors, which cross the membrane 7 times (7-M transmembrane proteins).
- Ligand binds to the receptor on the EC side that causes a conformation change in the 7-M protein, which allows the beta and gamma subunits of the G protein to bind to the IC side of the receptor.
This induces a conformation change in the alpha subunit. Thus, alpha subunit can bind GTP. In this activated state, the alpha subunit-GTP complex is liberated, and becomes able to either stimulate or inhibit either an ion channel or enzyme in the intracellular side of the membrane.
After this action, GTP is converted to GDP, alpha subunit binds to gamma and beta again, and G protein gets back to its resting state.
G protein – ion channel examples
Phospholipase C mechanism (PLC)
-The activated G protein stimulates enzyme phospholipase C of the membrane, which synthesizes two molecules from the membrane integrated phosphatidylinositol-bisphosphate in several consecutive steps. These products will serve as intracellular secondary messengers:
• 1: IP3 (1,4,5-trisphosphate)
– IP3 binds to the IP3 receptor located on the surface of the calcium sequesters (sarcoplasmic reticule, calciosomes). IP3 receptor is also an ion channel; IP3 opens it, and increases cytoplasmic calcium level. As a result, a set of cellular effects is generated.
• 2: DAG (diacylglycerol).
– DAG has a behaviour in the cells similar to that of cAMP, but it activates not type A protein kinases but rather type C ones (PKC), triggering several phosphorylation (activation) pathways of the cell leading to the biological effects.
G-protein – PLC examples
Phospholipase A2 (PLA2)
The activated G protein may control phospholipase A2 (PLA2) acitivty also a membrane enzyme on the innder surface. PLA2 is responsible for cleaving the membrane phospholipids and producing arachidonic acid molecules. Arachidonic acid is the substrate for futher synthesis of a set of biologically active IC agents or mediators (leukotrienes, lipoxins, prostaglandins, thromboxanes
- Final products of Gs protein activated phospholipase A2 pathway (lipoxins, leukotrienes, prostacyclins, prostaglandins, thromboxanes) have extremely widespread effects. They have a very short half-life (seconds, some minutes, exceptionally 20-30 min). In most cases they have an autocrine effect. Besides their paracrine action they exert hardly any endocrine effects, because they are very quickly degraded in the plasma.
- It is also characteristic of the final product, that despite their lipid solubility, they also have surface receptors, and they exert their effect on the cells through G protein dependent cAMP or IP3/DAG activation.
- For further details see chapter: Autacoids, eicosanoids.
Glutamate-sensitive receptors
-Post-synaptic membrane-integrated cation channels
3 main groups according to glutamate antagonists:
- NMDA receptor (N-metil-D-aspartate)
- -Binding of Mg2+ → receptor closed
- -Mg2+ dissociation → receptor activated
- AMPA receptor (alpha-amino 2 hydroxy, 5 methyl, 4 isooxazoloproprionic acid)
- Kainate receptor
