Glutamate and GABA Amino Acid Neurotransmitters, Receptors, and Drugs PT 1 Flashcards
Up to Pg.8 F Benzodiazepines
All CNS neurons carry receptors for
inhibitory and excitatory amino acid neurotransmitters
- aprox 1/3 brain and SC neurons release glutamate
- aprox 1/3 brain and SC neurons release GABA
Two main amino acid neurotransmitters maintaining balance between excitation and inhibition in normal brain function
- glutamate
- GABA
Important inhibitory amino acid neurotransmitters in vertebrate CNS
- GABA
- Glycine
GABA mechanism of action
- Opens Cl- permeable GABAa and GABA c channels
- activates metabotropic receptors that couple to G proteins these GABAb receptors serve inhibitory fxs at pre- and post- synaptic sites
GABA stands for
Gamma-amino butyric acid
drugs that target GABA receptors
- increase CNS inhibition mainly through allosteric mechanisms
- decrease anxiety (anxiolytic drugs)
- produce sedation
- anesthesia
- some used as anti-convulsants
Mechanisms of drug action GABA receptor targeting drugs
- direct agonists
- allosteric agonists
- allosteric antagonists
- non-competitive
- uncompetitive types inhibition
main excitatory amino acid neurotransmitter CNS
L-glutamate
L-glutamate effect on what receptors
activates excitatory receptors channels:
- AMPA-
- kainate-
- NMDA-type receptors
- Metabotropic glutamate receptors couple to G-proteins
Metabotropic glutamate receptors and G-proteins
- Metabotropic glutamate receptors coupled to G-proteins
- can have inhibitory and excitatory fxs depending on which G-protein its coupled to
Inhibition of of excitatory receptors in CNS
- decreases activity in CNS pathways that contain them
- Particularly true of NMDA type glutamate receptors
NMDA receptors clinically
of interest b/c found pain pathways and their inhibition -> amnesia
GABA fxs where
- principle inhibitory neurotransmitter or brain interneurons
- main inhibitory amino acid neurotransmitter in dorsal half spinal cord (DH)
- GABA-containing projection neurons (Purkinje neurons of cerebellum)
types GABA receptors
- GABAa receptor
- GABAb receptor
- GABAc receptor
GABAa and GABAc receptors
anion permeable ion channels complexes of 5 protein subunits
GABAb receptor
- coupled to G-proteins
- indirectly coupled via G-protein signaling pathway to voltage-dependent Ca2+ channels (presynaptic) and K+ channels (post synaptic)
which receptors most important numerically and most diverse and why
GABAa b/c composed of 6alpha, 4 beta, and 3 gama subunits
GABAa receptor activation
- GABA released
- GABAa receptor activated
- GABAa receptor opens intrinsic channel
- Flux Cl- ions across plasma membrane increases
5a. If cell resting potential less negative than Ecl cell hyperpolarized
5b. If cell resting potential more negative than Ecl cell will depolarize
6b. cell membrane potential negative to action potential threshold
what is affect of GABAa receptor activation and why
Ecl more negative than threshold action activation so effect GABAa receptor activation is to keep cell membrane potential negative to action potential threshold
Br- clinical significane
GABAa and glycine channels permeable to anions their high Br- permiablity has been exploited to treat canine epilepsy
effect of Br- entry through Cl- channels
Br- through Cl- channels hyper polarizes neurons and makes them less excitable
GABAa receptor fx enhanced by lg # drug types including
- anti-convulsants (anti-epileptics)
- anti-anxiety drugs (anxiolytics)
- barbiturates (sedatives, anticonvulsants, anesthetics)
- injectable anesthetic agents (etomidate, propofol)
- inhalation anesthetics (isoflurane, halothane ect.)
GABAb receptors pre or postsynaptic
theyre both
activation postsynaptic GABAb receptors causes
- increase in K+ permeablity -> hyperpolarization
GABAergic terminals (release GABA) and GABAb receptor
receptor activation -> decrease Ca2+ permeability -> decreases NT release
GABAb receptor fxly important where
in SC and other pts of brain
GABAc receptors mainly found where
retina
GABAc receptors structure
-closely resemble GABAa receptors but distinshuised from GABAa group bc contain rho (p) subunits
GABAc receptor pharmacology
- has distinct pharmacology bc rho subunit
- ivermectin kills parasites by inhibiting their muscle activity
GABA metabolism facts
- pt of pentose shut pathway
- synthesis metabolically favored bc ATP generated
GABA metabolism synthesis
L-glutamate-> GABA
catalyzed by glutamate decarboxylase (GAD)
GABA metabolism breakdown
GABA -> succinic semialdehyde catalyzed by GABA transaminase (GABA-T)
GABA breakdown and synthesis requires
pyridoxal (Vit B6) as a cofactor
Synaptic activity termination GABA
- terminated by reuptake through specialized transporters
- high affinity reuptake mainly into neuronal presynaptic terminal
- glial cells have lower affinity transporters
GABAa receptor agonists endogenous
GABA
GABAb receptors agonists endogenous
GABA
GABAc receptors agonists endogenous
GABA
GABAc receptors agonists synthetic
ivermectin
GABAa receptor antagonists cause
seizures
GABAa receptor allosteric modulators mechanism of action
- multiple discrete allosteric sites on GABA receptor-channel complex allosteric modulators enhance GABAa responses
Examples GABAa receptor allosteric modulators
- Alcohol
- Benzodiazepines
- Barbituates
- Steroid hormones
- Inhalation anestetics
- Newer injectable anesthetics
Alcohol GABAa allosteric modulator
Ethanol low dose -> - decreased anxiety - elevates mood - promotes sociability Ethanol higher doses - decreases brain activity
Benzodiazepines GABAa allosteric modluator
minor tranquilizers treat anxiety and pre-anestehtics
ex. Diazepam
Barbiturates GABAa allosteric modulators
- important as tranquilizers, pre-anestetic sedatives, short acting injectables used for induction
- pentobarbital = used for euthanizing in high doses
Steroid hormones GABAa allosteric modulators
- endogenous metabolites of progesterone and deoxycortisone potentiate GABAa mediated inhibition in manner similar to barbiturates
Inhalation anesthetics GABAa allosteric modulators
- interact in sterospecific manner with specific sites on GABAa subunits and potentiate GABAa- mediated inhibition at concentrations that = anesthetic doses in animals
Newer injectable anesthetics GABAa allosteric modulators
- etomidate and propofol
- interact with GABAa receptors at allosteric sites and potentiate GABAa mediated inhibition in CNS
phenobarbital does what acts where
- anti-seizure drug
- acts at allosteric site called barbiturate site
Injectable anesthetics example and act where
- act at allosteric barbiturate site
- act directly at neurotransmitter receptor site as direct agonist
ex. Thiobarbital
