Channels + Receptor types Flashcards
1
Q
K+ Channels
A
- Voltage-gated ion channel
- Most diverse family of ion channels
- More than 70 different genes encode K+ channels-alpha subunits in human genome
- Regulates cell excitability through:
+ Frequency + Action potential shapes
+ Hormone secretion
+ Neurotransmitter secretion
+ Membrane potential - Can have homomeric or heteromeric assembly
- Example drug acting on K+: Minoxidil
2
Q
Na+ Channels
A
- Voltage-gated ion channel
- First members of ion channel superfamily discovered
- Present in membrane of most excitable cells
- Less diverse + encoded by at lease 10 genes
- Comprise of 1 pore-forming alpha-subunit, which may be associated with either 1 or 2 beta-subunits
- Example drug acting Na+: Lidocaine
3
Q
Ca2+ Channels
A
- Voltage-gated ion channel
- Present in membrane of most excitable cells
- Forms hetero-oligomeric complexes, alpha-1 subunit is pore-forming + provides extracellular binding sites for all agonists + antagonists
- Has 3 families
+ High voltage activated dihydropyridine-sensitive channels (L-type + CaV1x channels)
+ CaV2x channels
+ Low voltage activated (T-type + CaV3x channels) channels - Example drug acting on Ca2+: Verapamil
4
Q
Nicotinic ACh Receptors (nAChr)
A
- LGIC
- First to be cloned + studies
- Structure was found by x-ray crystallography
- Each subunit has 4 transmembrane (TM) domains
- TM2 from each subunit lines ion channel pore
- Na+ (Gated ion) flows along its conc. gradient, with ACh acting as the ligand
- Causes depolarisation of cell
- Has fast action mechanism
- Different nAChrs exist, depending on which subunits are assembled into the complex ie Muscle subtype, A CNS subtype
- Example durg acting on nAChr: Succinylcholine
5
Q
Voltage-gated ion channel
A
- 18% of drugs target this family
- Helps manage ionic homeostasis, without them, ions will naturally repel from the cell
- Movement of ions is based on the charge inside and outside the cell + counter-charges
6
Q
Ligand-gated ion channel (LGIC)/Iontropic receptors
A
- Ligand binds to trigger conformational cahnge to become “conducting”
- Heteromic assembly (4-5 subunits)
- Integral membrane proteins that contain a pore which allows regulated flow of seleceted ions accross plasma membrane
- Ion flux is passive + driven by electrochemical gradient for permanent ions
- Mediates fast synaptic transmission on a millisecond timescale in nervous system
7
Q
G Protein-Coupled Receptor
A
- Characterised by 7TM domains
- Couple to G proteins to initiate signal transduction
- Activated by photons:
+ Photons
+ Hormones
+ Peptides
+ Peptidases - Largest family of cell-surface receptors
+ Approx. 800 genes
+ Approx. 400 non-olfactory genes, 120 which are “orphan receptors” (We don’t know what orphan genes do” - Currently represent of 50%+ of current drug targets ie Stomach ulcers, allergies, hypertension, migraines, glaucoma
- There are 6 classes of GPCR
8
Q
Enzyme-Coupled Receptor
A
- Are coupled/linked to an enzyme activity
- Has 6 classes dependent on activity + structure have been identified
+ Receptor tyrosine kinases
+ Tyrosine kinase-associated receptors
+ Receptor-serine/threonine kinases
+ Histidine-kinase-associated receptors
+ Receptor guanylyl cyclases
+ Receptor-like tyrosine phosphatases
9
Q
Nuclear Receptors
A
- Genome sequencing predicts 48 receptors
- All are structurally related (3 domains)
- Up to half are termed as Orphan receptors ie endogenous ligand has yet to be identified
- Function as either homo-/heterodimers
- Sometimes termed ligand-activated gene regulartory proteins (Transcription factors ie glucocorticoid receptor)
- Located in cytosol or nucleus, but not associated with lipid proteins
- Has 6 families
+ Thyroid receptor-like
+ Retinoid x Receptor-like
+ Oestrogen receptor-like
+ Nerve growth factor IB-like
+ Steroidogenic factor-like
+ Germ cell nuclear factor-like
10
Q
The 6 classes of GPCR
A
- There are 6 classes of GPCR classification based on sequence homology + functional similarity: \+ Class A: Rhodopsin-like \+ Class B: Secretin-like \+ Class C: Metabotropic glutamate/pheromone \+ Class D: Fungal pheromone \+ Class E: cAMP receptors \+ Class F: Frizzled/Smoothened \+ Unclassed - Classes A-C are the major classes
11
Q
Class A GPCR receptors
A
- Named after prototypical GPCR Rhodopsin
- Includes:
+ Adrenorecpetors
+ Histamine receptors
+ Dopamine receptors - Structure includes:
+ Short N-terminus
+ Agonists bind with extracellular loops + TM domains
+ C-terminal tail
+ Intracellular loops - Majority of prescribed GPCR drugs target Class A
12
Q
Class B GPCR receptors
A
- Named after secretin (ofc)
- Includes:
+ Secretin receptors
+ Calcitonin receptors
+ Glucagon receptors - Structure includes:
+ Larger glubular N-terminus where drugs bind
+ Extracellular + Intracellular loops
+ TM domains + C-terminal tail - Has far fewer approved drugs
13
Q
Class C GPCR receptors
A
- Named after metabotropic glutamate receptors
- Includes:
+ Metabotropic glutamate
+ GABAb receptors - Structure includes
+ Very large N-terminal domain for agonist binding to form obligatory dimers
+ C-terminal tail
+ Extracellular + Intracellular loops - Few small molecule drugs on market
14
Q
Receptor tyrsine kinases
A
- Phosphorylates tyrosine residues when substances are acted on the receptor
- Usually actiaveted by secreted growth factors + hormones
- Important examples of substances include:
+ Epidermal Growth Factor
+ Platelet-Derived Growth Factor
+ Vascular Enpthelial Growth Factor
+ Insulin - Many subclasses of receptor tyrosine kinase receptors
15
Q
Glucocorticoid receptors
A
- Targets for therapy
- Natural glucocorticoids include cortisol + corticosterone
- Effects are largely immunological + metabolic
- Involved in inflammatory disorders of gut, rheumatoid, arthritis, autoimmune diseases
- Immunological effects due to upregulation of anti-inflammatory proteins ie lipocartins
- Lipocartions suppress phospholipidase A2
+ Phopholipidase A2 contributes to inflammation by producing key intermediate molecule arachidonic acid - Drugs acting on glucocorticoid receptors:
+ Dexamethasone
