Superfamily 1 Flashcards
What is the simplest definition of superfamily 1 receptors?
Chemically gated (receptor operated) ion channels
How many subunits does a receptor in superfamily 1 have?
Five subunits
Made up of M1, M2, M3, M4 (transmembrane alpha helices)
Where is the agonist binding site found on this type of receptor?
On the extracellular N-terminal
N-terminal is frequently glycosylated
What is the molecular structure of SF 1?
2nd TM alpha helix from each sub unit contributes to channel lining
Allosteric interactions between lipid bilayer and hydrophobic amino acids in 4th TM alpha helix
Cytoplasmic loop between TM3 and TM4 alpha helices
Give an example of a SF 1 receptor
Nicotinic cholinoceptor
Why are there subtypes of Nicotinic cholinoceptors?
Several types of alpha and beta subunits occur
Alpha 1-10 and beta 1-4
Encoded by different genes
Subunit expression varies between tissues
Given examples of some of the pentameters in SF1
NMJ - 2 alpha1, 1 beta1, 1 delta + 1 other subunit
Alpha4beta2 hetero, alpha7 homo and alpha9alpha10 heteropentameters common in CNS
Alpha3beta4 hetero in autonomic ganglia
Alpha7 homo also present in endothelial immune cells
Give a basic explanation of how Nicotinic cholinoceptors work?
Nicotinic receptors contain two alpha subunits, both of which must bind to a molecule of ACh in order to activate the receptor and open the channel
Describe how the Nicotinic cholinoceptor changes shape
5 subunits turn slightly in relation to each other once the agonist binds
The receptor protein structure unfolds and exposes the charged upper region of the channel pore
An ion flux occurs through the channel
Altered membrane potential cause the cell excitability
How does subunit composition and ratio change the properties of a receptor?
Can influence the affinity for ACh/ nicotine
Influence cation selectivity
Influence susceptibility to desensitisation
Opportunity for more diverse allosteric regulations at multiple site
Subunit mutations implicated in neurological disorders
What therapeutic application do partial agonists selective for alpha4 beta2 heteropentameters have?
Smoking cessation: verenicline
Reduces acute nicotine craving when quitting
Reduces chronic Nicotinic reinforcement (pleasure reward)
What therapeutic effects do antagonists selective for alpha9 alpha10 heteropentameters have?
Subcutaneous / intramuscular administration
Acutely alleviate pain resulting from traumatic, inflammatory or metabolic neuronal injury
What therapeutic benefits do +ve allosteric modulators at alpha7 containing pentameters have?
Attenuate cognitive decline in dementia
What does galantamine treat and why is described as multi target?
Alzheimer’s
Acts as a nAChR allosteric modulator and a cholinesterase inhibitor
What does bupropion treat and why is it described as multi target?
Smoking cessation and depression
Acts as a nAChR allosteric modulator and a monamine re-uptake inhibitor
What does carbamazepine used for and why is it described as multi target?
Anticonvulsant
Acts as a nAChR allosteric modulator and a voltage gated sodium channel blocker
Give a 2nd example of an SF1 receptor
GABA A receptor / chloride channel
Describe SF1 GABA A receptors
A family of receptors for inhibitory neurotransmitter gamma aminobutyric acid (GABA)
Widely distributed in the CNS
Give a basic explanation of how diazepam works
Targets GABA A receptors as a positive allosteric modulator
What is the molecular structure of GABA A?
2 alpha, 2 beta and 1 gamma/theta/pi/lambda subunit
How does the GABA A receptor react/ interact?
Convulsants (picrotoxin) block channel pore
Cytoplasmic loop between TM3 and TM4 alpha helices of beta subunit subject to phosphorylation
Allosteric regulation by general anaesthetics, ethanol, neuro steroids
Lipid bilayer exerts direct allosteric interaction
How does the opening of GABA A Cl- channels alter the body?
Drugs that open the chloride channels are called positive allosteric modulators
They have a CNS depressant action, sedative and anxiolytic effects
Give examples of drugs that act on the GABA A receptor
Barbiturates
Propofol
Benzodiazepines
Alcohol
Define what an overdoes is
The excessive stimulation of GABA A chloride channels
What happens during an overdose?
Usually seen in combination with alcohol/ alcoholism
Coma, respiratory depression, may result in death
What is strychnine an example of?
A glycine receptor
Chloride channel
Describe strychnine
Is a receptor antagonist
Neurotoxic to motor nerves in the spinal cord (excitatory effect)
Used as a pesticide to kill small rodents by muscle spasm, convulsions, choking, respiratory arrest
Give an example of a serotonin SF 1 receptor
Serotonin 5-HT3 receptor
Cation (sodium/potassium) channel
Distinct from other non SF1 serotonin receptors
