Membrane Receptors Flashcards
what are the 4 main receptor types?
1) Ligand-gated ion channels
2) Nuclear receptors
3) Kinase-linked receptors
4) G-protein-coupled receptors (GPCRs)
what are ligand-gated ion channels?
- ionotropic receptors (transmembrane ion-channel proteins which open to allow ions such as Na⁺, K⁺, Ca²⁺ etc)
- Hormone/neurotransmitter binds to the receptor causing conformation change in ion channel (open) - this causes influx of a selected ion.
- Speed: very fast – few milliseconds
- Example: NAChR
what are nuclear receptors?
Located in the nucleus- can cross PM (lipophilic)
usually transcription factors
- First messenger passes through membrane and into nucleus, binding to a transcription factor which then binds to the section genome to cause effect by altering genetic activity.
- Speed: Slow
- Example: Oestrogen Receptors
what are kinase- linked receptors?
- GF (1st messenger) binds to receptor
- Causes dimerisation of receptor
- Tyrosine kinase regions are activated and become phosphorylated (6 x ATP)
- RTK is now fully activated
- Cellular proteins become activated which causes a cascade which initiates a cellular response
- Speed: Slow
- Example: Tyrosine kinase receptor
- If these receptors are mutated, they cause cell proliferation and so are often implicated in various form of cancer.
what are G-protein-coupled receptors?
- They are the largest family of membrane receptors mediating effect of many hormones and neurotransmitters. They are the biggest targets for drugs.
- They don’t carry any enzymatic activity themselves- cannot produce any secondary messengers on their own
- They interact with another intermediate transducer (G-proteins) which go and modulate the functions of other receptors which leads to a cellular effect
what is the structure of G-protein receptors?
- The receptor spans the plasma membrane 7 times
- They have 7 domains- 7 alpha helices weave in and out
- G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits). Alpha and gamma subunit use lipid anchors- membrane bound.
- Speed: Fast (seconds)
- Example: Muscarinic Ach Receptor
what is the mechanism of GPCRs?
Alpha subunit in an inactive state has GDP bound to it and in an active state has GTP bound to it.
1) Agonist binds to receptor causing it to undergo a conformational change into a more active conformation thus allowing it to bind with the heterotrimeric G proteins.
2) Binding causes G-protein to open, releasing GDP and causing GTP to bind to the alpha subunit (that GDP was previously bound to)
3) G-protein now dissociates with the receptor and the alpha subunit separates from the beta and gamma subunits.
4) The subunits then interact with other effectors such as enzymes and ion channels initiating a biological response.
5) After a while the alpha subunit will hydrolyse GTP into GDP again then the GDP will associate with the alpha subunit and the beta and gamma subunit will also associate again allowing the cycle to continue. This is a type of catalytic activation.
what are the different G- protein alpha subunit?
- G alpha s - stimulates Adenylyl cyclase
- G alpha i/o - inhibits of Adenylyl cyclase
- G alpha q/11 - stimulates Phospholipase C Beta
most important ^^ - G alpha 12/13 - regulates small g proteins for cytoskeleton contraction
G beta gamma - regulate ion channels and enzymes like PLCb
what is adenylyl cyclase activated by?
Effector enzyme activated by G alpha S
what does adenylyl cyclase do?
what enzyme breaks down cAMP?
produces a secondary messenger.
AC catalyses the conversion of ATP into cyclic AMP (cAMP)
The enzyme cAMP phosphodiesterase (PDE) breaks the cyclic- phosphate bond and converts cyclic AMP into AMP (now inactive) - essentially stopping the reaction from reoccurring.
what is phospholipase C activated by?
activated by G alpha Q
what does G alpha Q do to phospholipase C?
1) Gαq stimulates the enzyme PLC on the membrane which uses phospholipids as substrates e.g. PIP2.
2) PLC hydrolyses the phospholipid’s phosphate bond to produce two different mediators- DAG + InsP3 (both secondary messengers)
3) InsP3 activates the channels of the ER allowing calcium to be released from through pumps from the ER lumen.
4) The rapid release of calcium into the cytosol alongside DAG activate kinases such as PKC which then phosphorylates several substrates producing a biological response
what causes glycogen metabolism?
adrenaline and glucagon- bind to GPCR in liver cells
in the liver
explain the mechanism of hormone regulation of glycogen metabolism
1) Starts with G-protein coupled receptors (Gs) which stimulate AC to form cAMP which then activates PKA (A stands for AMP)
2) PKA phosphorylates phosphorylase kinase enzyme which becomes active as phosphorylase kinase P.
3) PKP then phosphorylates glycogen phosphorylase b into the active a form.
4) This enzyme then removes one glucose each from the glycogen chain.
5) AT THE SAME TIME, glycogen synthase is phosphorylated by protein kinase A to P glycogen synthase (inactive) hence stopping all glycogen synthesis.
how is smooth muscle tone regulated?
▪ G alpha S coupled receptors increase cAMP concentration which lead to an inhibition of MLCK and the stimulation of the MLCP which catalyses the dephosphorylation of MLC causing relaxation.
▪ Gq coupled receptors cause an increase in intracellular calcium concentration (calcium released for intracellular stores in the ER).
▪ The calcium ions bind with calmodulin and the complex stimulates MLCK.
▪ MLCK then phosphorylates MLC leading to smooth muscle contraction.
what are examples of reversibility in protein phosphorylation?
protein kinase- adds phosphate activating a protein
protein phosphatase- removes phosphate
what do hormones released by the pituitary act on?
Pretty much all hormones released by the anterior pit gland act on GPCR with G alpha s subunit.
explain the cAMP/PKA pathway in endocrine cells
1) GPCR is activated
2) The alpha subunit then interacts with enzymes AC.
3) AC converts ATP into cAMP which binds to protein kinase activating Protein kinase A (PKA)
4) The activated PKA enters into the nucleus and helps activate CREB (transcription factor)
5) This produces a response which results in the secretion of hormones or cell replication.
6) When reducing cAMP, PDE degrades cAMP converting it into AMP to shut off signalling cascade.
what are activating mutations?
cause constitutive activation of the pathway leading to tumour formation and hyper function (e.g. having a hyper active thyroid or producing too much of a particular enzyme) of the cells
what are inactivating mutations?
lead to hormone resistance (e.g. cascade of reactions is stopped)
explain the process of TSH receptor signalling in the thyroid
TSH (released via pituitary gland) binds to Gs-protein coupled receptors on the surface of thyroid cells leading to the production of cAMP which activates PKA - CREB activation (TF)
This leads to an increased replication of thyroid cells and it also induces the synthesis and release of thyroid hormones into the bloodstream.
