Receptor structure and cell to cell communication Flashcards
Cell to cell communication
- Synthesis of signalling molecule
- Release of signalling molecule
- Transport to site of target cell
- Detection of signal by specific receptor
- Alteration in cell function after activation of signal-receptor complex
- Removal of signal and termination of response.
Autocrine signalling
Signal controls activitg of signalling cell (self-regulates).
Example - NA acts on presynaptic alpha2 adrenoceptors to inhibit NA release. (auto-inhibitory feedback).
Cell to celk signalling via plasma membrane attached proteins
Extracellular membrane receptors and signalling molecules expressed on cell membranes are tethered.
Example - ephrins and ephrin receptors
Paracrine signalling
Short distance
Example - ACh release from a neuron at nmj, actjng on adjacent target cells (skeletal muscle)
Endocrine signalling
Long distance
Example - hormone secretion into blood by endocrine gland, acts on distant target cells.
Two types of receptor systems receive extracellular signals
Intracellular receptors
Plasma membrane receptors
Intracellular receptors
Hydrophobic signal molecule binds to a carrier molecule and is carried in blood.
Receptor-hormone complex crosses the plasma membrane at the site of action and binds to receptor protein in cytosol.
Active receptor translocates to nucleas, binds to DNA and acts as a transcription factor. Gene transcription occurs, New proteins are made.
Plasma membrane receptors
Hydrophilic signal molecule (ligand) cannot cross the membrane. Binds to the plasma membrane receptor proteins at site of action. This activated receptor generates an intracellular chemical signal (second messenger).
Receptors serve to…
Specifically detect/bind to the initial signal (agonist)
Couple agonist-bound receptor to the correct intracellular signalling pathway.
Amplify agonist binding event into a detectable intracellular response. ( same agonist can have fast or slow onset depending on receptor).
General principles of extracellular receptor structure
Ligand binding to hydrophilic molecules
General principles of transmembrane receptor structure
Mostly hydrophobic (to cross lipid bilayer) Key charged residues control binding/ion passage Helical structure
General principles of intracellular (cytosolic) receptors
Interaction with signalling pathways
Hydrophilic
Site of feedback control.
Classification of receptors
- Ligand-gated ion channels
- Receptors that have enzymatic activity
- Receptors non-covalently associated with enzymes
- G-protein coupled receptors
Nicotinic ACh as a prototypical ligand-gated ion channel receptor
Rapid onset, rapid offset.
nAChRs are non-selective cation channels
Nerve impulses cause vesicle fusikn with presynaptic membrane.
ACh in cleft jnfreases dramatically.
ACh receptors transiently increase sodium influx and potassium efflux.
The resulting depolarisation opens voltage-gated sodium channels resultjng in an action potential.
Actikn potentials and muscle contraction
Response must be fast on fast off to allow complex movement.
There is a high abundance of nAChRs in electrical organs.
nAChRs are pentamers (5 subunits) the subunits cluster to form a ring, this creates a pore in membranes to allow ion passage.
Common structure of nAChR subunits
There is an extracellular N terminus, 4 transmembrane spanning helices and an extracellular c terminus. The 4 helices are named M1 -M4 and are all alpha helices.
M2 is orientated into the channel pore (ACh binding determines shape of M2 helix)
Glycosylation and disulphide bonds (extracellularly between N terminus and M1) confer stability in a harsh environment so the receptor is ready to bind hormone.
Molecular basis of nAChRs opening
Resting state - each subunit has a conserved leucine in their M2 helix, these line the centre of the pore to form a gate.
Specific Glu and Thr residues in the pore also provide electron pairs.
Theseattract cations and exvlude anions.
Two ACh molecules bind to the hydrophilic extracellular region of each receptor.
This causes the helices to tilt away from each other from approx 1millisec. Leucines are mo longer blocking the pore and the gate opens, cations pass down concentration gradient into cell. Helices move towards eachnother agajn causjng gate to close and ACh to dissociate.
Ligand gated ion channels function at fast synapses
Excitatory receptors - ACh, glutamate, serotonin
Inhibitory receptors - glycine and GABAa
