Pharmacology lecture 5- transduction mechanisms Flashcards
Where are receptors located
on the cell membrane have an extracellular domain, a transmembrane domain, and an intracellular domain.
What binds to the extracellular site ?
chemicals, drugs or transmitters
Signalling may then be initiated across the membrane to activate secondary mechanisms leading to a response.
Types of post-synaptic effect
the post synaptic cell may be:
A skeletal muscle - the muscle membrane will be excited, fire action potentials and the muscle will contract.
- A gland cell will be excited and begin to secrete.
- Pacemaker cells in the heart may increase or decrease their firing rate
- Postsynaptic neurones in the CNS may be excited or inhibited
Signal transduction
In order to produce these effects the signal (action potential) received by the receptor on the post-synaptic membrane must be communicated to appropriate sites in the cell by a process
The final response depends on the:
Type of cell
Type of receptor
Type of the chemical/transmitter
Example of cellular response
Example of cellular response:
Contraction
Relaxation
Secretion
Growth
Change in metabolism
What is another word for type 1 receptors and what are they part of
ionotropic receptors
part of ligand gated ion channels
Activation leads to change in conductance of ions
Receptors on which fast neurotransmitters act, eg. Nicotinic acetylcholine receptor (nAChR), GABAA receptor, glutamate receptors.
Receptor is part of ligand-gated ion channel protein.
Response very fast (millisecond) eg. Nerve-nerve or nerve-skeletal system signalling.
At rest the channel is closed. When agonist binds to the receptor, a conformational change in protein will occur which opens the ion channel thus ions can flow through pore down their electrochemical gradient.
Example- acetylcholine
(released from the parasympathetic system) is a transmitter in the body at the skeletal neuromuscular junction.
Binds to nicotinic receptors (nAChR)
Opens the channel for 1-2 msec (mean open time), and Causes an increase in Na+ & K+ (cation).
Net inward current carried mainly by Na+ depolarises the cell membrane →release of Ca2+ from SR → Ca2+ binding to troponin C → activation of myosin ATPase → contraction of skeletal muscle.
Typical ionotropic 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
Thus, only +ve 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.
Ion flow through the ionotropic receptor
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
ﻻ -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 GABAA receptor complex appears to have distinct binding sites for benzodiazepines, barbiturates (anxiolytic/hypnotic/anticonvulsants agents), ethanol, inhaled anaesthetics, etc.
Glutamate
An excitatory amino acid transmitter in the CNS, acting on NMDA receptors.
Causes opening of channels permeable to Na+/K+/Ca2+ in the membrane.
Leads to fast synaptic transmission as a result of fast depolarisation.
Type 2- G-protein coupled receptors (GPCRs) or metabotropic receptors or 7 transmembrane receptors
The receptor couples to G-protein leads to a response.
The largest family including receptors for many hormones and slow transmitters, eg. Muscarinic acetylcholine receptors (mAChR), adrenergic receptors, and chemokine receptors.
Response takes sec to mins to hours
G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome.
The term “7TM receptor” is commonly used interchangeably with “GPCR”, although there are some receptors with seven transmembrane domains that do not signal through G proteins.
Typical metabotropic receptor
7 alpha helices in the protein structure create a large transmembrane protein.
This is a neuropeptide Y receptor, but the classical example (a ß[beta] adrenoceptor for NAdr) has the same structure.
The receptor is coupled to G-proteins (see later).
type 2
The G-protein consists of three subunits (α, β, γ), which are anchored to the membrane through attached lipid residues.
Coupling of the α subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular GTP;
The α-GTP complex then dissociates from the receptor and from the βγ complex, and interacts with a target protein (target 1, which may be an enzyme, such as adenylate cyclase, or an ion channel).
The βγ complex may also activate a target protein (target 2).
The GTPase activity of the α subunit is increased when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α subunit reunites with βγ.
