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PH3501- Neuropharmacology > Lec 6- GABA > Flashcards

Lec 6- GABA Flashcards

1
Q

Synthesis of GABA and glycine

A
  • GABA is formed from glutamate by enzyme Glutamic acid decarboxylase GAD
  • All enzymes that release GABA contain GAD
  • GABA is broken down by enzyme GABA-T (GABA transaminase)
  • Synthesis and metabolism linked to Kreb cycle
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2
Q

Synthesis and metabolism of GABA: I

A
  • GABA is synthesised from glutamate by the enzyme glutamic acid decarboxylase (GAD)
  • GAD is found only in those neurons which synthesise GABA and thus the location is a valuable identifier of GABAergic neurons
  • GABA is metabolised by the ubiquitous enzyme GABA transaminase
  • GABA is release by interneurons- released locally to act on neurones close to the release
  • GAD is anaerobic while GABA transaminase is aerobic thus after death the levels of GABA in the brain increase very rapidly
  • Inhibitors of GAD will cause a decrease in the levels of brain GABA and cause convulsions
  • Several inhibitors of GABA transaminase have been developed which lead to increases in the levels of brain GABA; these compounds are anti-convulsants
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3
Q

Storage and release of GABA and glycine

A
  • Both GABA and glycine appear to be stored in synaptic vesicles and their release is by Ca2+ dependent exocytosis
  • Both GABA and glycine are removed from the synaptic cleft by active re-uptake processes
    • This is the means by which their actions are terminated subsequent to their release
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4
Q

Reuptake of GABA and glycine

A
  • Both GABA and glycine are removed from the synaptic cleft by active reuptake processes
  • This is the means by which their actions are terminated subsequent to their release
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5
Q

Inhibitory amino acid receptors

A
  • Glycine receptors are ionotropic receptors
  • GABA receptors are of 2 types:
    • GABAA receptors are ionotropic- allow ions to pass (Cl-), directly linked to ion channels
    • GABAB receptors are metabotropic- GPCR linked to 2nd messengers= change the metabolism of cell= Much slower due to cascade
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6
Q

Glycine receptors

A
  • The glycine receptor is an ionotropic receptor and is closely related structurally to the GABAA receptor
  • Glycine receptors are found mainly in the spinal cord; the convulsant drug strychnine (death by asphyxiation- muscle contraction) is a competitive glycine antagonist
  • The channel is anion specific
  • The functional receptor is composed of 5 subunits which surround the ion channel; there are 3 alpha and 2 beta subunits in the adult receptor
  • The natural agonist is glycine but the receptor may also be activated by beta-alanine and taurine
  • Strychnine is the most potent selective antagonist with affinities in the range of 5-15 nM
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7
Q

GABAA and GABAB receptors -EXAM

A
  • GABAA receptors are found mainly post-synaptically and are directly coupled to chloride channels the opening of which reduces neuronal excitability; the convulsant bicuculline (convulsant) is a competitive antagonist, picrotoxin blocks GABAA receptor channel
  • GABAB receptors are mainly responsible for pre-synaptic inhibition and are coupled to 2nd messengers
  • Baclofen is an agonist
  • Antagonist include phaclofen, 2-OH, saclofen
  • Can cause subsequent inhibition of neurotransmitter- If GABA = autoreceptor- it does this by blocking Ca2+= stop release of Ca2+ dependent exocytosis
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8
Q

Classification of GABA receptors- GABAA effects

A
  • Post-synaptic inhibition
  • Increase Cl- conductance
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9
Q

Classification of GABA receptors-GABAA Agonist

A
  • GABA = +
  • Muscimol = +
  • Baclofen = -
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10
Q

Classification of GABA receptors- GABAA Antagonists

A
  • Bicuculline= +
  • Picrotoxin= +
  • Phaclofen= -
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11
Q

Classification of GABA receptors- GABAB Effects

A
  • Pre-synaptic inhibition
  • Decreased Ca2+ conductance
  • Increase in K+ conductance
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12
Q

Classification of GABA receptors- GABAB Agonist

A
  • GABA= +
  • Muscimol= -
  • Baclofen= +
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13
Q

Classification of GABA receptors- GABAB Antagonists

A
  • Bicuculline= -
  • Picrotoxin= -
  • Phaclofen= +
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14
Q

Comparison of the distribution of GABAA and GABAB receptors in the cerebellum

A
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15
Q

GABAB receptor: I

A
  • GABAB receptors are metabotropic receptors being coupled to second messenger systems
  • Activation of the receptors located on pre-synaptic terminals suppress the release of neurotransmitter by inhibition of inward Ca2+ conductance
  • Activation of the receptors located post-synaptically produces a long-lasting hyperpolarisation by increasing K+ conductance
  • The functional receptor is composed of 2 protein subunits: GABABR1 + 2
  • These proteins are 7 transmembrane proteins with amino acid sequence homology of about 35%
  • The distribution of the 2 proteins appears to be similar and it appears that both are expressed together to provide the pharmacology that we expect of GABAB receptors in vivo
  • This is the only G-protein coupled a receptor presently known that functions as a heterodimer; subunit associate via their C-termini
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16
Q

GABAB receptors in the CNS

A
  • GABAB receptors may be involved in
    • Control of epilepsy
    • Regulation of the hypothalamic-pituitary axis
    • Enhancement of anti-depressant drug action
    • Suppression of cocaine withdrawal symptoms
    • Alleviation of pain
17
Q

GABAA receptors in the CNS- GABAA receptors are involved in

A
  • Sedation
  • Anxiety
  • Muscle relaxation
  • Convulsive activity
  • Amnesia making midazolam in particular a valuable pre-anaesthetic
18
Q

GABAA receptors: I

A
  • Major inhibitory amino acid receptor in the brain
  • Channel is anion specific (Cl-)
  • GABA activation causes an inhibitory post-synaptic potential (IPSP)
  • Agonists: GABA, muscimol
  • Antagonist: bicuculline
  • Channel blocker: Picrotoxin
  • Change of chloride gradient occurs in both early development and epilepsy
19
Q

GABAA receptors: II - GABAA receptors also have binding sites for

A
  • Benzodiazepines- diazepam
  • Barbiturates
  • Neurosteroids- alfoxalone (anaesthetic)
20
Q

GABAA receptor- additional binding site

A
  • Benzodiazepines
    • potentiate the action of GABA by shifting the GABA dose-response curve to left- (Same amount of GABA = greater response)
    • Increase frequency of channel opening
  • Barbiturates
    • Potentiate actions of GABA by shifting the dose-response curve to the left and increasing the maximum response
    • Increase channel open lifetime
  • Steriods
    • Potentiate actions of GABA
    • Increase channel opening frequency and open lifetime
21
Q

Allosteric modulation of the GABAA receptors

A
  • A-is the theoretical dose-response curve which induces an increased chloride conductance as the concentration of GABA is increased
  • B- represents the leftward shift in that dose-response curve which would be seen in the presence of a benzodiazepine agonist
  • C- represents the leftward shift and increased maximum induced by pentobarbitone
22
Q

Accessory site agonist of GABAA receptors

23
Q

Evidence to support this mechanism of action

A
  • There is a strong correlation between the affinity of individual agonist benzodiazepines for their binding site in the brain and the therapeutic dose required to produce their overt effects
  • Flumazenil (Anexate) acts as an antagonist at the benzodiazepine site and blocks the effects of both the agonist and inverse agonist benzodiazepines
  • The effects of the benzodiazepine agonist are directly correlated with blood levels of the drug; the relief of anxiety is immediate
24
Q

Inverse agonist at the benzodiazepine site

A
  • In 1980 a compound, ethyl b-carboline-3-carboxylate (b-CCE) was discovered that competitively displaced the benzodiazepines from their binding sites in brain membranes
  • Behavioural experiments showed that this compound had effects diametrically opposed to those of the classical benzodiazepines: these compounds are now referred to as inverse agonist
25
Q

Efficacy spectrum of benzodiazepine receptor site ligand

26
Q

Structure of GABAA receptor

27
Q

Cloning of GABAA receptor subunits

A
  • Several classes of GABAA receptor subunit have been cloned
    • Alpha subunit of which there are 6 isoforms
    • Beta of which there are 3 isoforms
    • Gamma subunit of which there are 3 isoforms- the gamma unit is located within the synapse itself
      • Delta= extrasynaptic location
  • Functional receptors are made up of 5 subunits arranged pseudosymmetrically around the integral ion channel
  • The most common GABAA receptor of the mammalian brain consists of 2X a1, 2X b2 and 1X y2 subunits
  • The different sub-units, give slightly different physiological responses
28
Q

GABAA receptor subunit isoform

29
Q

Why all these subunits

A
  • The functional characteristics of a particular GABAA receptor are defined by its precise subunit composition
  • The alpha subunit is important in the recognition of the benzodiazepines
  • The b-subunits are important in the recognition of the natural agonist GABA- must have 2 units
  • The y subunit is an important structural subunit
30
Q

Synthesis and metabolism of GABA: II

A
  • GAB in anaerboic while GABA transaminase is aerobic thus after death the levels of GABA in the brian increase very rapidly
31
Q

Different Alpha units = different actions

A
  • Alpha-1= sedative- Mainly in the cerebellum, hippocampus, globus Palabras
  • Alpha 2,3= Anxiolytic- 2= hippocampus ; 3= Amygdala
  • Alpha 5= striatum
  • Alpha 5= CA1, CA3
  • Alpha 6= cerebellum
  • These are dynamic, they change during time, pathology (epilepsy), hormonal cycles

PH3501- Neuropharmacology (28 decks)

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