Ligand gated ion channels Flashcards
give examples of ligand gated ion channels and what ions they gate
GABAa and glycine receptors: Cl- influx leads to hyperpol
nAChRs, P2X (ATP), AMPA (glutamate), and 5-HT3: Na+ influx: depol contraction
NMDA (glutamate): Ca2+ influx: enhanced NT release
Families of LGICs and their structure
Cys-loop: 4TM pentamer EC n and IC c terminal e.g., nAChRs, 5-HT3, GABAA, glycine, ZAC re
glutamate family: 3TM tetramer EC N IC C terminal e.g., NMDA, AMPA, kainate
P2X family: 2TM trimer EC n and IC c terminal e.g., P2X
Therapeutic exploitation of P2X
Clinical trial for cough
give examples for the Therapeutic exploitation of glutamate family
piracetam PAM for AMPA receptors to treat myoclonus (involuntary twitches)
AMPA antagonist perampanel for seizures.
NMDA antagonists (memantine, ketamine) for dementia or anaesthesia
give examples for the Therapeutic exploitation of Cys-loop family
5-HT3 antagonists (ondansetron) for chemo nausea
nAChR antagonists (e.g., atracurium, pancuronium) for neuromuscular blockade in surgery, or agonists (e.g., nicotine and varenicline) for smoking cessation.
GABAA has PAM (e.g., benzos, barbiturates) for anxiety, depression, insomnia. 1 NAL (neutral allosteric)
what are the types of Allosteric modulators
PAM = enhances receptor function
NAM = inhibits receptor function
NAL = neutral - allosteric antagonist (binds with no effx blocks PAM and NAM
GABAA receptor structure and binding domains, and GABA synthesis
GABA synthesised from glutamate by the two isoforms (GAD1/2) of glutamic acid decarboxylase.
4TM pentamer. Large EC N-terminus with a cys-loop
composed of 19 potential subunits, in different combinations.
Binding of orthosteric ligands occurs at the interface between the B+/a- subunits
5 allosteric domains: Cl- Channel, picrotoxin, barbiturates, steroid site, and benzodiazepine (BZD)
Orthosteric ligands: GABA, muscimol, bicuculline (antagonist)
GABA chloride channel allosteric modulation
NAM: penicillins (uncompetitive, requiring open channel)
Picrotoxin allosteric modulation
NAM: picrotoxin, and pentylenetetrazole: convulsants
Barbiturate allosteric modulation
PAM: phenobarbital, thiopental
depressants/sedative: anti epileptic
GABAA agonist at high conc
GABAA Steroid allosteric modulation
PAM: progesterone, testosterone, alphaxalone
anaesthetic sedative
GABAA general anaesthetic site
PAMs: etomidate, propofol, ethanol
anaesthetics
BZD allosteric modulation
PAMs: diazepam, alprozolam
sedative/hypnotic
NALs: flumazenil (reverses BZD effects)
NAM: DMCM
inverse agonist, causes excitation
BZD allosteric site forms between the gamma+/alpha- subunits
