Glutamate and GABA Amino Acid Neurotransmitters, Receptors, and Drugs PT 1

Question 1

All CNS neurons carry receptors for

Answer 1

inhibitory and excitatory amino acid neurotransmitters

• aprox 1/3 brain and SC neurons release glutamate
• aprox 1/3 brain and SC neurons release GABA

Question 2

Two main amino acid neurotransmitters maintaining balance between excitation and inhibition in normal brain function

Answer 2

• glutamate

- GABA

Question 3

Important inhibitory amino acid neurotransmitters in vertebrate CNS

Answer 3

• GABA

- Glycine

Question 4

GABA mechanism of action

Answer 4

• 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

Question 5

GABA stands for

Answer 5

Gamma-amino butyric acid

Question 6

drugs that target GABA receptors

Answer 6

• increase CNS inhibition mainly through allosteric mechanisms
• decrease anxiety (anxiolytic drugs)
• produce sedation
• anesthesia
• some used as anti-convulsants

Question 7

Mechanisms of drug action GABA receptor targeting drugs

Answer 7

• direct agonists
• allosteric agonists
• allosteric antagonists
• non-competitive
• uncompetitive types inhibition

Question 8

main excitatory amino acid neurotransmitter CNS

Answer 8

L-glutamate

Question 9

L-glutamate effect on what receptors

Answer 9

activates excitatory receptors channels:

• AMPA-
• kainate-
• NMDA-type receptors
• Metabotropic glutamate receptors couple to G-proteins

Question 10

Metabotropic glutamate receptors and G-proteins

Answer 10

• Metabotropic glutamate receptors coupled to G-proteins

- can have inhibitory and excitatory fxs depending on which G-protein its coupled to

Question 11

Inhibition of of excitatory receptors in CNS

Answer 11

• decreases activity in CNS pathways that contain them

- Particularly true of NMDA type glutamate receptors

Question 12

NMDA receptors clinically

Answer 12

of interest b/c found pain pathways and their inhibition -> amnesia

Question 13

GABA fxs where

Answer 13

• 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)

Question 14

types GABA receptors

Answer 14

• GABAa receptor
• GABAb receptor
• GABAc receptor

Question 15

GABAa and GABAc receptors

Answer 15

anion permeable ion channels complexes of 5 protein subunits

Question 16

GABAb receptor

Answer 16

• coupled to G-proteins
• indirectly coupled via G-protein signaling pathway to voltage-dependent Ca2+ channels (presynaptic) and K+ channels (post synaptic)

Question 17

which receptors most important numerically and most diverse and why

Answer 17

GABAa b/c composed of 6alpha, 4 beta, and 3 gama subunits

Question 18

GABAa receptor activation

Answer 18

1. GABA released
2. GABAa receptor activated
3. GABAa receptor opens intrinsic channel
4. 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

Question 19

what is affect of GABAa receptor activation and why

Answer 19

Ecl more negative than threshold action activation so effect GABAa receptor activation is to keep cell membrane potential negative to action potential threshold

Question 20

Br- clinical significane

Answer 20

GABAa and glycine channels permeable to anions their high Br- permiablity has been exploited to treat canine epilepsy

Question 21

effect of Br- entry through Cl- channels

Answer 21

Br- through Cl- channels hyper polarizes neurons and makes them less excitable

Question 22

GABAa receptor fx enhanced by lg # drug types including

Answer 22

• anti-convulsants (anti-epileptics)
• anti-anxiety drugs (anxiolytics)
• barbiturates (sedatives, anticonvulsants, anesthetics)
• injectable anesthetic agents (etomidate, propofol)
• inhalation anesthetics (isoflurane, halothane ect.)

Question 23

GABAb receptors pre or postsynaptic

Answer 23

theyre both

Question 24

activation postsynaptic GABAb receptors causes

Answer 24

• increase in K+ permeablity -> hyperpolarization

Question 25

GABAergic terminals (release GABA) and GABAb receptor

Answer 25

receptor activation -> decrease Ca2+ permeability -> decreases NT release

Question 26

GABAb receptor fxly important where

Answer 26

in SC and other pts of brain

Question 27

GABAc receptors mainly found where

Answer 27

retina

Question 28

GABAc receptors structure

Answer 28

-closely resemble GABAa receptors but distinshuised from GABAa group bc contain rho (p) subunits

Question 29

GABAc receptor pharmacology

Answer 29

- has distinct pharmacology bc rho subunit | - ivermectin kills parasites by inhibiting their muscle activity

Question 30

GABA metabolism facts

Answer 30

- pt of pentose shut pathway | - synthesis metabolically favored bc ATP generated

Question 31

GABA metabolism synthesis

Answer 31

L-glutamate-> GABA | catalyzed by glutamate decarboxylase (GAD)

Question 32

GABA metabolism breakdown

Answer 32

GABA -> succinic semialdehyde catalyzed by GABA transaminase (GABA-T)

Question 33

GABA breakdown and synthesis requires

Answer 33

pyridoxal (Vit B6) as a cofactor

Question 34

Synaptic activity termination GABA

Answer 34

- terminated by reuptake through specialized transporters - high affinity reuptake mainly into neuronal presynaptic terminal - glial cells have lower affinity transporters

Question 35

GABAa receptor agonists endogenous

Answer 35

GABA

Question 36

GABAb receptors agonists endogenous

Answer 36

GABA

Question 37

GABAc receptors agonists endogenous

Answer 37

GABA

Question 38

GABAc receptors agonists synthetic

Answer 38

ivermectin

Question 39

GABAa receptor antagonists cause

Answer 39

seizures

Question 40

GABAa receptor allosteric modulators mechanism of action

Answer 40

- multiple discrete allosteric sites on GABA receptor-channel complex allosteric modulators enhance GABAa responses

Question 41

Examples GABAa receptor allosteric modulators

Answer 41

- Alcohol - Benzodiazepines - Barbituates - Steroid hormones - Inhalation anestetics - Newer injectable anesthetics

Question 42

Alcohol GABAa allosteric modulator

Answer 42

``` Ethanol low dose -> - decreased anxiety - elevates mood - promotes sociability Ethanol higher doses - decreases brain activity ```

Question 43

Benzodiazepines GABAa allosteric modluator

Answer 43

minor tranquilizers treat anxiety and pre-anestehtics | ex. Diazepam

Question 44

Barbiturates GABAa allosteric modulators

Answer 44

- important as tranquilizers, pre-anestetic sedatives, short acting injectables used for induction - pentobarbital = used for euthanizing in high doses

Question 45

Steroid hormones GABAa allosteric modulators

Answer 45

- endogenous metabolites of progesterone and deoxycortisone potentiate GABAa mediated inhibition in manner similar to barbiturates

Question 46

Inhalation anesthetics GABAa allosteric modulators

Answer 46

- interact in sterospecific manner with specific sites on GABAa subunits and potentiate GABAa- mediated inhibition at concentrations that = anesthetic doses in animals

Question 47

Newer injectable anesthetics GABAa allosteric modulators

Answer 47

- etomidate and propofol | - interact with GABAa receptors at allosteric sites and potentiate GABAa mediated inhibition in CNS

Question 48

phenobarbital does what acts where

Answer 48

- anti-seizure drug | - acts at allosteric site called barbiturate site

Question 49

Injectable anesthetics example and act where

Answer 49

- act at allosteric barbiturate site - act directly at neurotransmitter receptor site as direct agonist ex. Thiobarbital