physiology and pharmacology Flashcards
drug targets:
proteins: receptors, enzymes, transport proteins, ion channels
nucleic acids: DNA, RNA
receptor =
a protein that is involved in the normal process of cell communication
embedded in the plasma membrane or within the cell cytoplasm or nucleus
enzymes as drug targets -
inhibitors - can be competitive/non competitive
e.g. acetylsalicyclic acid (asprin) is a non competitive inhibitor of cyclooxygenase
false substrates - drugs converted by enzymes to generate abnormal product
modification of pro-drugs - requires chemical modification before becoming active
transporters as drug targets -
inhibitor - block transport
e.g.cocaine inhibits noradrenaline
false substrate - drug competes with normal substrate leading to accumulation of an abnormal compound
ion channels as drug targets -
ion channel blockers - drug binds in the channel pore to affect ion permeation
e.g. tetrodotoxin blocks Na channels
ion channel modulators - bind to the ion channel protein to affect gating
receptors as drug targets -
agonists - ligand that binds and activates a receptor to produce a response
antagonist - ligand that binds to a receptor and prevents its activation by an agonist, lacks efficacy
nuclear receptors -
inside the nucleus, act as transcriptional regulators
- steroid hormones
- thyroid hormones
- vitamin D
- fatty acids
ligand gated ion channels -
- regulated by the binding of a specific agonist
- mediate signalling in nervous system
comparison:
ligand gated ion channel -
location: membrane
effector: ion channel
coupling: direct
e. g: nicotinic acetylcholine receptor, GABAa receptor
structure: oligomeric assembly of subunits surrounding central pore
comparison:
G protein coupled receptor -
location: membrane
effector: channel or enzyme
coupling: G protein or arrestin
e. g: muscarinic acetylcholine receptor, adrenoreceptor
structure: oligomeric assembly of subunits comprising 7 transmembrane alpha helices with intracellular G protein coupling domain
comparison:
receptor kinases -
location: membrane
efffector: protein kinases
coupling: direct
e. g: insulin, growth factors, cytokine receptors
structure: single transmembrane helix linking extracellular receptor domain to intracellular kinase domain
comparison:
nuclear receptors -
location: intracellular
effector: gene transcription
coupling: via DNA
e. g: steroid receptors
structures: monomeric structure with receptor and DNA binding domains
hydrophobic ligands -
passively diffuse across the cell membrane use intracellular receptors function as activators or repressors of genes
ligand regulated transcription factors -
control cell proliferation, development, metabolism and reproduction
nuclear receptor superfamily:
steroids - oestrogen, progesterone
non steroidal lipophilic regulators - fatty acids, thyroid hormones, vitamin D3
orphans - no ligand or ligand unknown
signal transduction pathways:
second messengers…
- diffusible signals
- bind target proteins to change conformation and activity
- highly localised diffusion field
e.g. calcium ions + cAMP
cAMP as a second messenger in signal transduction pathways…
cyclic adenosine monophosphate
- binds regulatory subunits of protein kinase A
- subunits dissociate relieving inhibition of PKA
calcium ions as a second messenger in signal transduction pathways…
- enter cell via ion channels or are released from the endoplasmic reticulum via ion channels
- IP3 (inositol triphosphate) is released from plasma membrane and stimulates the opening of the ion channels
- calcium can interact directly with effector proteins to induce conformational change or can act through intermediate calmodulin protein to modify the activity of the effector
signal transduction pathways:
protein phosphorylation…
= the addition of phosphate to specific sites on proteins as a regulatory mechanism in signal transduction
- changes bulk and charge of the amino acid residue side chain
- addition of a phosphate causes structural alteration
= changes protein activity
signal transduction pathways regulate activity of:
transcription factors - increase gene expression
translation factors - increase protein expression
proteolytic enzymes - decrease protein expression
cytoskeletal proteins - regulate motility and shape
cell proliferation and death effectors
G protein coupled receptors respond to…
neurotransmitters - acetylcholine, GABA
hormones - glucagon, adrenaline
large glycoproteins - thyroid stimulating hormones
G protein coupled receptors couple to…
heterotrimeric G protein which controls the activity of an effector protein
G proteins comprise of…
a family of membrane resident proteins that recognise activated GPCRs and pass on the message to the effector systems that generate a cellular response
the G protein consists of 3 subunits (alpha, beta, gamma) which are anchored to the membrane through attached lipid residues
G protein coupled receptors respond to ligands by…
changing conformation
GTP binding causes dissociation of beta/gamma subunits and release of GDP = leading to an active state
G proteins are regulated by…
GEFs = guanine nucleotide exchange factors
- stimulates G protein to assure it acheives active conformation (stimultes loss of GDP and gain of GTP)
G protein activation cycle:
1) when a GPCR is activated by an agonist, a conformational change occurs
2) coupling of the alpha subunit to an agonist occupied receptor causes the bound GDP to exchange with intacellular GTP
3) the alpha-GTP complex dissociates from the receptor and interacts with a target protein, leaving a beta/gamma complex which also activates a target protein
4) the GTPase activity of the alpha subunit is increased when the target protein is bound leading to hydrolysis of GTP TO GDP = the alpha subunit reunites with beta/gamma
