Transduction Mechanisms Flashcards
How does binding of a chemical/ hormone/transmitter/ drug to a receptor initiate a response?:
~Chemicals, drugs or transmitters bind to the extra cellular site of the receptor
-signalling may then be initiated across the membrane to activate secondary mechanisms leading to a response.
Types of post-synaptic effect:
examples of post synaptic;
→ skeletal muscle: the muscle membrane will be excited, fire action potentials and the muscles contract
→ A gland cell will be excited and begin to secrete
→ Pacemaker cells in the heart may increase or decrease their firing rate.
→ Postsynaptic neuron’s in the CNS may be excited or inhibited.
How is the effects of a signal (action potential) produced?
To produce these effects the signal (action potential) received by the receptor on the postsynaptic membrane, must be communicated to appropriate sites in the cell by a process known as= signal transduction .
Synaptic transmission:
~ cellular responses are rapid
~some effects such as those mediated by thyroid or steroid hormones, occurs over hours or days
~so different types of linkage between receptor occupation and observed response are involved
What does the final response depend on?
The type of cell
The type of receptor
Type of the chemical/transmitter
Example of cellular response:
Contraction, relaxation, secretion, growth and change in metabolism
4 classes/types of receptors are distinguished:
Based on molecular structure and nature of this linkage (transduction mechanisms)
Further flashcards explain the 4 types of
Type 1- Receptors which are part of ligand-gated ion channels (ionotrophic receptors):
-activation leads to change in conductance of ions
-receptors on which fast neurotransmitters act e.g. nicotine, acetylcholine, receptor, GABA receptor, glutamate receptors
-receptor is part of ligand- gated ion channel protein
-Response is very fast (millisecond) e.g. nerve cell, skeletal system signalling
At rest the channel is closed when a agonist binds to the receptor, a conformational change in protein will occur which opens the ions channel thus ions can flow through pore down their electrochemical gradient.
Typical iontropic receptor:
5 protein subunits (each of which consists of 4
alpha helices as shown) come together to form a transmembrane
structure with a central pore.
This is a nicotinic receptor
The nicotinic receptor has a central ‘pore’ which carries negative charge
-only two ions (Na and K+ ) can get through when the pore is opened
The top region of the protein has a binding site for ACh, when ACh binds, the conformation of the protein shifts, so that the pore opens. When no ACh is bound, the conformation of the protein is such that no ions can get through.
Open for only 1-2msecs.
Examples of ionotropic receptor:
E.g. acetylcholine- transmitter at skeletal neuromuscular junction
-binds to nicotinic receptors (nAchR)
-opens channel for 1-2 sec (mean open time) and causes an increase Na+ and K+ (cation)
-net inward current carried mainly by Na+ depolarises the cell membrane- release the ca2+ from SR- ca2+binding to troponin C- activation of myosin ATPase contraction of skeletal muscle
Nicotinic acetylcholine receptor:
(a typical ligand-gated ion channel) in side view (left) and plan view (right). The five receptor subunits (a2, B, y, 0) forn cluster surrounding a central transmembrane pore, the lining of which is formed by the M2 helical segments of each subunit. These contain a preponderance of negatively charged amino acids, which makes the pore cation selective. There are two acetylcholine binding sites in the extracellu portion of the receptor, at the interface between the a and the adjoining subunits. When acetylcholine binds, the kinked a helices either straighten or swing out of the way, thus opening the channel pore.
Ion flow through the ionotropic receptors :
• Both Na+ and K+ can flow through the ion channel but move in opposite directions through the channel.
• Since the concentration gradient for Na+ is greater than for K+, entry of Na+ into the postsynaptic cell, predominates, Sodium entry causes the post-synaptic membrane to depolarise
Type 1:
Y -Aminobutyric Acid receptors (GABAA receptors):
• An inhibitory neurotransmitter in the CNS.
• Activation of the receptor on Cl channel protein by agonist opens the channel and Cl- ions enter the cell causing hyperpolarisation (inhibits depolarisation).
In addition to the GABA binding site, the GABA receptor complex appears to have distinct binding sites for benzodiazepines, barbiturates (anxiolytic/hypnotic/anticonvulsants agents), ethanol, inhaled anaesthetics, etc.
What is type 1:
Notes that various agonist drugs induce similar conductance with different mean open time. Due to a difference in closing rate constant- so agonists with low efficacy exhibit faster closing rate constants
Type 2-G protein coupled receptors or metabotrophic receptors or 7 transmembrane receptors
~receptors coupled to G protein leads to a response
~largest family including receptors for many hormones and slow transmitters
~response takes seconds,minutes,hours
~G protein coupled receptors are largest class of membrane proteins in human genome. 7tm receptor which was used interchangeably with GPCR but some receptors 7 TM domains that do not signal through G proteins
Examples of metabotrophic receptors:
-GPCRs have common architecture, consisting of:
-Single polypeptide with an extracellular N-terminal
-An intracellular C-terminal
-7 hydrophobic TM domains (TM1-TM7) linked by 3 intracellular loops (ECL-1-ECEL3) and 3 intracellular loops (ICL1-ICL3)
-About 800 GPCRs- 50% sensory function
-mediating olfaction (400), taste(33), light perception (10), pheromone signalling (5)
