Receptors and signalling

how do drugs exert their action

how do drugs exert their action

by binding to proteins

4 classes of proteins targeted by drugs

ion channels, enzymes, ion channels receptors

what are ion channels

protein channels in the membrane that allow lipophobic /hydrophilic molecules through

which ion channels to drugs target

involved in neurotransmission

examples of drugs that target neurotransmission

sodium channel blockers

gabapentin

how does gabapentin work

targets voltage gated calcium ion channels to prevent its movement and prevent AP

role of receptor targeting

regulates cellular processes

enables communication between cells

enables coordination of tissue, organ and bodily responses

how do drugs causes side effects despite being targeted

off target effects can occur which occurs from interactions with receptors in multiple organs

what is an example of a drug and its side effects

opium has analgesic and euphoric effects but can cause constipation and respiratory diseases

how does opium use lead to addiction

activation of reward pathways and changes in receptor function (tolerance)

what is the cause of death in opium addicts

respiratory disease and suffer from chronic constipation

how do receptors help in drug function

allows for specificity in drug function

which type of receptor does not pass through the membrane

steroid

what do ionotropic, metabotropic and kinase linked receptors have in common

they are found on the cell surface and have transmembrane spanning segments of 20-25 hydrophobic amino acids

what is a feature and function of DNA linked receptors

regulates gene transcription

ligand must be able to cross the plasma membrane (lipophillic)

what is an example of a DNA linked receptor

oestrogen receptors

what is a ligand

any molecule that binds to the receptor

what is a Agonist

drugs or chemical mediators that bind to a receptor producing a response

examples of agonists

pilocarpine, nicotine, aCh, morphine

what is an antagonist

does not a cause a downstream response or prevents/ inhibits the response of an agonist e

examples of antagonists

atropine curare

how long is the signal transduction of ionotropic, metabotropic, kinase-linked and nuclear receptors

mms, s, hrs, hrs

what is an example of a LGIC

nicotinic ACh receptor

what is an example of a metabotropic receptor

Muscarinic ACh receptor

what is an example of a kinase-linked receptor

cytokine receptor

what is an endogenous receptor

a compound naturally produced by the body which binds and activates the receptor

what is the endogenous molecule for ionotropic receptors

small molecule chemical mediators not proteins

what happens when a molecule binds to an ionotropic receptor

central aqueous pore opens

how many transmembrane domains in GPCRS

7

what structure do GPCRs have

alpha helical structure

what is a heterotrimeric GTP binding protein

g protein

when do lignad gated ion channels open

when they are bound by an agonist

what does activation of an ionotropic receptor by excitatory neurotransmitters cause

membrane depolarisation and action potential firing

where are nicotinic acetylcholine receptors found?

neuromuscular junction, autonomic ganglion neuron, brain neurones

what is the agonist for NaChR

ACh and nicotine

what is the antagonist for NaChR

tubocurarine (curare)

examples of ionotropic glutamate receptors

AMPA and NMDA

what are the 2 most common receptors

ligand gates and G protein coupled

what are most hormones detected by

GPCRs

what is the structure of GPCRs

a single protein and spans the membrane 7 times

how do GPCRs work?

regulate effector proteins via heterotrimeric GTP binding protein

what is the structure of a g protein

1 alpha, 1 beta, 1 gamma (heterotrimeric)

how does signal transduction occur in GPCRs

via activation of g proteins

how are g proteins selective

they can be made up of 30 different alpha, beta and gamma units to make different g proteins which interact with different GPCRs and effectors

how many members of the GPCR family are there

800+

what do GPCRs respond to

hormones, inflammatory mediators and chemokines

why does GPCR signal transduction take longer than LGIC?

it is cascading and involves changing the function of different proteins

where is the ligand binding site in an opioid receptor

buried within the transmembrane receptors

what happens when the ligand is bound to a GPCR

it will make contact with several amino acids which influences the structure that the receptor will adapt

which effectors can g proteins control

ion channels, enzymes

types of ligand gated ion channels

cys-loop

ionotropic glutamate

P2x

calcium release

examples of cyc-loop type receptor & assembly

nAChR, GABAa 5HT3

pentameric

exmales of ionotropic glutamate type receptor and assembly

NMDA

tetrameric

example of P2X type receptor and assembly

P2XR

trimeric

examples of calcium release type receptor and assembly

IP3R, RyR

tetrameric

what are LGIC used for

fast synaptic transmission

what are the endogenous agonsists for LGIC

fast classical neurotransmitters stored in vesicles

what are LGIC composed of

3-5 subunits

how many transmembrane domains does each LGIC subunit have

2-5

when does a LGIC close

when the agonist is removed or the receptor enters a desensitised state

what causes changes in the excitability of a cell

ions flowing through open LGIC

what happens in the activation of ionotropic receptors for inhibitory neurotransmitters

membrane depolarisation is inhibited

action potential firing is reduced

what is an example of a receptor for an inhibitory neurotransmitter

GABAaRs expressed by the brain w

what is the agonist for GABAaRs

GABA, phenobarbitone

what is the antagonist for GABAaRs

Picrotoxin

what is phenobarbitone used for

epilepsy

what is the use of picrotoxin

CNS and respiratory system stimulant

what is myasthenia gravis

an autoimmune disease where the body creates antibodies to skeletal nicotinic acetylcholine receptors

what are the symptoms of myasthenia gravis

increasing muscle weakness, eye drooping

how many people suffer with myasthenia gravis

1 in 2000

how is myasthenia gravis treated

anti-cholinesterase to prevent the breakdown of ACh, and immunosuppressants

example of an anticholinesterase

neostigmine, pyridostigmine

why are some GPCRs referred to as orphans

because the ligand they respond to has not been identified

when does signal transduction occur

following an agonist binding to a GPCR and activation of a g protein

one G protein is used by _______ receptor

more than one

how do g proteins achieve signal transduction

by undergoing an enzymatic cycle

which g protein subunits interact with effectors

alpha and beta

what happens when the agonist is bound to the GPCR

it stabilises the helices and activates signalling

what happens when the antagonist is bound to the GPCR

it interacts differently with amino acids and adopts a shape not conducive to signalling

what happens after agonist binding to GPCRs

signal transduction via g proteins which control the function of effectors

how many types of g proteins are there

20

what are second messengers

small diffusible molecules that spread signals

how do noradrenaline and adrenaline work

via g protein coupled receptors

where is the binding site of the g protein

the alpha subunit

what is the role of GDP

associated with the inactive GPCR

how is GDP suited to bind to an inactive GPCR

has a very high affinity to beta-gamma subunits in GPCRs

how is the g protein activated after agonist binding

agonist becomes very attracted to the alpha subunit and associates with it

causes a change in the structure of alpha lowering GDP affinity for GTP instead

GTP replaces GDP and g protein is activated

what do g proteins need to be activated

GTP

what part if the g protien is a GTPase

alpha

what is a GTPase

binds and hydrolyses GTP

what is the limiting factor in GPCR signalling

receptor number

how is the g protein inactivated

GTPase activity is activated in alpha and GTP loses a phosphate to become GDP

conformational changes increase attraction to beta-gamma subunit and reforms heterotrimeric g protein

alpha` subunit no longer attracted to effector molecule and beta gamma no longer regulating protein

Gs protein

stimulates adenyl cyclase to make cAMP

Gi protein

inhibits adenyl cyclase leading to a cAMP decrease

Gq

increases phospholipase C

increased IP3 and DAG

increases calcium intake

what is phospholipase c

an enzyme effector modulated by g protein

which subunits regulates the activity of enzymes

alpha

what causes an increase in pKA activity

increased cAMP

what is cAMP

a second messenger that can diffuse into the nuclease to regulate proteins

what is cAMP broken down by and into

phosphodiesterase into 5AMP