Signal Transduction: Proteins And Pathways Flashcards
Signal transduction definition
The conversion of biotic and abiotic information from outside a cell to inside, which can then be interpreted and acted upon
The binding of a signalling molecule to a receptor leads to signal transduction within the cell often involving phosphorylation
What are extracellular signalling molecules
What is a signal
- molecules such as hormones and neurotransmitters that are synthesised and packaged into secretory vesicles
- Secreted by specialised signalling cells
- A signal produces a specific response in target cells
- These target cells receive the signal by expressing receptor proteins that bind the signal
How is the signal processed by a cell (hydrophobic and hydrophilic signals)
Hydrophobic:
1) steroids, retinoids and thyroxine can diffuse through the plasma membrane and bind to cystolic receptors
2) THe receptor-signal complex moves into the nucleus and binds transcriptional control regions influencing levels of expression
Hydrophilic:
1) small molecules, peptides and proteins bind to a cell surface receptor
2) activates receptor and triggers a conformational change
3) Triggers signal transduction proteins e.g. kinase enzymes to begin phosphorylation OR small-molecule second messengers e.g. Ca2+
4) effector proteins are activated and they consequently modify cystolic proteins in short term influencing cellular function, metabolism
5) effector can cause long term alterations by moving into nucleus and influencing expression
What are the four types of signalling
1) Endocrine signalling is long-distance signalling
2) involves hormone secretion in the bloodstream
3) the hormone conc is usually dilute by the time it reaches the receptor
4) paracrine signalling is short-distance signalling
5) Involves exocytosis of ligand and diffusion into an adjacent target cell
6) Autocrine signalling is when a cell signals to itself
7) involves exocytosis of ligands that bind to its own receptors
8) this is a form of reinforcement of a particular cellular pathway
9) eicosenoids are fatty acid derivatives released upon tissue damage, and autocrine signalling helps the process of inflammation/pain/fever to occur
How are proteins most often regulated
- Cytosolic proteins often regulated by phosphorylation and dephosphorylation by kinase and phosphatase enzymes
What other types of regulation for signal transduction
- G proteins are molecular switches
- GTPase activity promote GDP bound G proteins, which is their inactive form
- The removal of GDP and replacement with GTP leads to active G proteins, catalysed by GEF (guanine exchange factor) activity
- GTP bound G proteins often activate effector proteins in response to the stimulus
- GPCR (g protein coupled receptors/heterotrimeric G proteins) are surface receptors that receive ligand information and initiate many intracellular cascades
G protein linked signalling
- G protein coupled receptors are sensitive to various extracellular ligands including hormones, peptides and neurotransmitters
- Upon binding, GPCRs undergo conformational changes leading to alterations to Heterotrimeric G proteins
- In the inactive state Heterotrimeric G proteins are bound to GDP and upon activation by GEFs, GDP is replaced with GTP and the G protein can interact with intracellular effector proteins
- Effector proteins such as adenylyl cyclase, phospholipase C and ion channels, whilst secondary messengers can also be triggered by G proteins such as Ca2+, cAMP. These secondary messengers activate kinases and phosphatases leading to protein phosphorylation and modulation with protein activity
- This can lead to changes in gene expression, metabolism, ion channel activity, proliferation
- Hydrolysis of GTP bound G protein leading to conformational reformation of inactive GDP-G protein and deactivation of effector proteins
Enzyme linked receptor signalling
Signalling dependent on multicomplex disassembly
The two factors that determine the way the cell responds to signalling molecules
- The type of receptor that is bound (e.g. skeletal muscle has a different receptor and leads to contraction)
- The nature of the intracellular machinery (e.g. acetylcholine on the heart leads to relaxation whereas on salivary glands secretion is the process triggered)
How can signalling occur through multiple cell types
- Nerve terminal secretes acetylcholine as a form of sympathetic nervous stimulation to endothelial cells
- Binds to NO synthase, producing NO
- NO diffuses and binds to an enzyme that converts GTP into cyclic GMP (cGMP)
- Rapid relaxation of smooth muscle leads to increase blood flow due to effects of cyclic GMP
How does Viagra work
- Phosphodiesterase type 5 (PDE5) is an enzyme that breaks down cyclic guanosine monophosphate (cGMP)
- CGMP is responsible for vasodilation and relaxation of smooth muscle
- Inhibition of PDE5 leads to higher concentrations of cGMP in penile blood vessels when sexual stimulation initiates NO release
What is the commonest attachment that occurs between cytosolic proteins and the inner plasma membrane
- Lipid-anchored membrane proteins where the lipid is embedded in one leaflet and anchors the polypeptide which is not in contact with the bilayer
- Acyl anchors: myristate + palmitate
- Kinases anchored via acylation
Describe the components of GPCR signal transduction pathways
All share these elements:
1. A receptor containing seven membrane-spanning a helices
2. A heterotrimeric g protein, which cycles between active and inactive forms
3. A membrane-bound effector protein
4. Proteins that participate in desensitisation of the signalling pathway
5. (Second messengers often phosphatases, kinases and calcium are often common)
The G-protein activation cycle
- Cycle includes an inactive receptor, a trimeric G protein containing Ga, Gb and Gy subunits and a GDP/GTP binding site, and an inactive effector protein
- Binding of ligand causes conformational change in receptor
- Activated receptor binds to Ga subunit
- Causes conformational change in Ga causing dissociation of GDP
- GTP binding to Ga triggers dissociation of Ga subunit from the receptor and the Gby subunits
- GTP-Ga subunit binds to effector activating it
- Hydrolysis of GTP to GDP terminates the signal transduction and causes Ga to dissociate from effector and re associate with Gby subunits
