GABA and Glutamate 2 Flashcards
GABA A receptor discovery 1987
GABA A receptors are ligand-gated chloride channels
Cl- entry hyperpolarises (stabilises) the membrane
The postsynaptic response is an ipsp (Ipsp = inhibitory postsynaptic potential)
Examples of GABA A receptor modulators:
Benzodiazepines
There is an endogenous source somewhere in the body that has not yet been identified
Benzos increase the activity of GABA and extend it increasing inhibition
Effective for epilepsy and sedation
Barbiturates
Steroids
Ethanol
Picrotoxin, pentylenetetrazol – used in experiments
Anaesthetics (propofol etc.)
Zinc ions
THIP (Gaboxadol) sedation drug
Glutamate receptor
GluA2 subunits contain an amino acid that blocks Ca intake
Difference between life and death arguably
Path clamping
Technique used to measure neural activity
Fine electrode inserted into cell to measure proper neuronal function
It is possible to measure a single channel within a cell
Sackman et al won the Nobel prize in Germany for this
Molecular actions of drugs
Benzodiazepines
- anxiolytic, hypnotic, anticonvulsant etc.
- potentiate GABA responses
- increase frequency of Cl- channel opening
- ‘silent’ antagonists, inverse agonists
Barbiturates
- sedatives (‘hypnotics’), anaesthetics
- potentiate GABA responses
- prolong Cl- channel opening
- can open channel without GABA
Neurosteroids
- similar to barbiturates
Anti-epileptic drugs
GABA A receptor modulators:
- barbiturates (phenobarbitone)
- benzodiazepines (diazepam etc)
GABA-transaminase inhibitors
- vigabatrin
- GABA uptake inhibitors
Tiagabine
? Gabapentin – function currently unknown
History of benzodiazepines
Serendipitous discovery in 1950’s/1960’s
Chlordiazepoxide (®Librium), diazepam (®Valium)
Discovery of specific binding sites (1970’s)
Many ‘me-too’ follow-up drugs e.g. lorazepam (®Ativan)
Anxiolytics, hypnotics (e.g. nitrazepam =®Mogadon),
anticonvulsants (clobazam = ®Frisium)
Inverse agonists. Flumazenil = antagonist
Problems of tolerance and dependence
High therapeutic ratio of benzodiazepines
*Benzodiazepines are the most important class of anxiolytic (also hypnotic, anticonvulsant etc)
*Developed as safer alternatives to barbiturates
*More selective anxiolytic action
*Safer – higher therapeutic ratio
GABA A receptor diversity
Seven types of subunit: a, b, g, d, e, p and q
Different isoforms of subunits, e.g. a1-6 (16 total)
gamma subunit required for benzodiazepine activity
Different subunit combinations give rise to a range of different GABAA receptors mediating
different behavioural effects, e.g. sedation, hypnosis, anxiolysis, anticonvulsant, muscle relaxation
Actions of other modulators also dependent on subunit composition
GABA A receptors
GABAA receptor activation → fast ipsp’s
Increase in Cl- conductance
Pentameric structure
16 subunits (a1-6; b1-3; g1-3; d; e; p; q)
Typical constitution: two a; two b; one g
Two GABA binding sites
Many allosteric modulatory binding sites
Different subtypes mediate sedation, anxiolysis, induction of sleep etc?
Genetic studies on GABA A receptor types
*Gene-knockout and ‘knock-in’ strategies
*Ablation of individual receptor subunits
*Replacement of single amino acid codon
*Analyse changes to mouse pharmacology, physiology/behaviour
Initial results of genetic studies on GABA A receptor types
*In a1-point-mutated mice diazepam-induced sedation and anticonvulsant effects were attenuated
*Other effects of diazepam were unaffected, e.g.
- anxiolysis
- muscle-relaxant effects
- specific hypnotic effects
- ethanol potentiation
Roles of GABA A subtypes and suitable study approaches
*Genetic approach:
point mutations in mice to render particular receptor subtypes insensitive to diazepam
a1-containing receptors → sedation
a2-containing receptors → anxiolysis
a5-containing receptors → cognition
*Medicinal Chemistry
novel selective drugs; selectivity for a2 and/or a3 imparts anxiolytic activity; selectivity for a5- containing receptors enhances cognition (learning/memory)
