T1 Fricker- Hormonal Signalling

what are the different kinds of pathways in animal signalling?

in order of increasing distance:

• contact-dependent

• paracrine- short-distance localised signal

• endocrine- bloodstream-transported signal

• synaptic

describe steroid hormone signalling and how it works

• small + cheap to make (no N, P or S)

• hydrophobic = able to cross membranes independently

• persistent, generalised, long-term responses

• the steroid hormone detaches from its carrier protein in the blood, diffuses into the target cell and binds to an intracellular receptor, often displacing an inhibitor protein

• this activates the receptor (no signal amplification), exposing a DNA-binding site, so it can move into the nucleus and activate genes

what are the three classes of cell surface receptor?

• enzyme-linked receptors- binding of a ligand causes a conformational change in the receptor activating a catalytic domain, or recruiting/activating an enzyme eg. receptor tyrosine kinases (MAPKKK cascade)

• G-protein coupled receptors- binding of a ligand causes a conformational change in the receptor, which activates a trimeric G protein intermediate, activating an enzyme in turn eg. cAMP signalling

• ion channel receptors- binding of a ligand causes a conformational change that opens the channel for ion diffusion

describe enzyme-linked receptor signalling and an example

enzyme-linked receptors- binding of a ligand causes a conformational change in the receptor activating a catalytic domain, or recruiting/activating an enzyme

• most only have one transmembrane domain

example:

• receptor tyrosine kinases, activated (eg. by growth factors), assemble as dimers and autophosphorylate their cytoplasmic tails at tyrosine residues

• this scaffolding recruits a series of downstream components, including guanine exchange factors (GEFs), which temporarily activate small GTPases eg. Ras that swap GTP and GDP bound to proteins eg. Raf

• Raf is a mitogen-activated protein kinase kinase kinase (MAPKKK), which phosphorylates MAPKK twice, in turn phosphorylating MAPK twice, which phosphorylates + activates transcription factors (an amplification module)

describe G-protein coupled receptor signalling and two examples

G-protein coupled receptors- binding of a ligand causes a conformational change in the receptor, which activates a trimeric G protein intermediate, activating an enzyme in turn

• these receptors have 7 transmembrane alpha helix domains which bundle up

• the N-terminus and extracellular loops bind the ligand, which causes a conformational change in the C-terminus and cytoplasmic loops, allowing them to interact with a GDP-bound G-protein

• this changes its conformation so that it binds GTP (active)

• the alpha subunit dissociates and binds to a target enzyme (eg. PLC), and hydrolyses the GTP to activate it

• the other two subunits can also initiate signal transduction

example:

• in cAMP signalling, adrenaline is secreted from the adrenal medulla into the bloodstream in response to stress

• this binds to G-protein coupled receptors (sigmoidal binding) on the surface of muscle, liver and adipose cells

• this causes the activation of adenylate cyclase, which produces cyclic AMP

• this binds + activates protein kinase A (PKA), and releases it to phosphorylate phosphorylase kinase

• this in turn phosphorylates glycogen kinase which initiates glycogenolysis

• PKA also phosphorylates the receptor itself, inactivating + desensitising it

example:

• in the inositol signalling pathway, the activated G protein is what activates the PLC (not in fertilisation)

• this triggers calcium-induced calcium release to regulate many different factors

describe ion receptor signalling and four examples

• ion channel receptors- binding of a ligand causes a conformational change that opens the channel for ion diffusion

examples:

• the acetylcholine receptor is a pentameric ligand gated channel, with two acetycholine binding sites- ACh binding opens the channel to allow diffusion of ions through (primarily sodium because it is far from the equilibrium of the membrane potential)

• the GABA receptor is a pentameric ligand gated channel with one GABA binding site- GABA binding opens the channel for chloride ion diffusion to resist depolarisation of the membrane

• ionotropic glutamate receptors bind to glutamate, and are specific to different ions for depolarisation

• metabotropic glutamate receptors are G-protein coupled → activate ion channels

describe two examples of cross talk between signalling pathways

different signalling pathways can interact:

• eg. activates receptor tyrosine kinases (enzyme-linked receptors) assemble as dimers and autophosphorylate their cytoplasmic tails at tyrosine residues

• this can bind and activate IP3 kinase from the inositol signalling pathway

• this phosphorylates PIP₂ to produce PIP₃

• PIP₃ can act as a scaffolding protein for cytoskeletal interactions

• eg. metabotropic glutamate receptors are G-protein coupled, initiating the activation of adenylate cyclase, which produces cyclic AMP

• this binds + activates protein kinase A (PKA), and releases it to phosphorylate + open a sodium ion channel to cause membrane depolarisation