Successfully reported this slideshow.
Your SlideShare is downloading. ×

GABA.pptx

Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Ad
Upcoming SlideShare
angina ppt.ppt
angina ppt.ppt
Loading in …3
×

Check these out next

1 of 55 Ad

More Related Content

Recently uploaded (20)

Advertisement

GABA.pptx

  1. 1. GABA
  2. 2.  Introduction  Discovery  Synthesis, storage and degradation  Receptors  Neuropsychiatric implications  Drugs
  3. 3. Introduction  Gamma Amino Butyric Acid (GABA) is the major inhibitory neurotransmitter of the mammalian CNS.  It is broadly distributed in the brain.  GABA acts at inhibitory synapse in the brain by binding to specific transmembrane receptor in the plasma membrane of both pre and postsynaptic neuronal processes.  Implicated in broad range of neuropsychiatric disorders like seizures, anxiety disorders, schizophrenia, alcohol dependence etc.
  4. 4. Striatum:  GABAergic neurons directly project to the substantia nigra pars reticulata  Striatal GABergic neurons also project to the globus pallidus to synapse on the pallidal-subthalamic GABAergic neurons that regulate the excitatory output from the subthalamic nucleus. Cerebellum:  In cerebellum, GABAergic Purkinje cells are its main efferent system
  5. 5. Synthesis and Storage  Synthesised from amino acid L- Glutamic acid by the action of  Glutamic acid Decarboxylase (GAD) an enzyme present in neurons and peripherally in pancreatic islet cells and body fluids.  It catalysis the removal of α- carboxyl group.  It is most highly concentrated in the substantia nigra & globus pallidus nuclei of the basal ganglia, followed by
  6. 6.  GABA transporter (GAT)  GAT 1 is identified as a presynaptic receptor. While GAT 2-4 receptor location have yet to be identified.  Tiagabine blocks GAT1 receptor – increase in synaptic GABA concentration – anticonvulsant action.
  7. 7.  GABA is catabolised by GABA transaminase (GABA-T).  GABA-T is a cell surface, membrane bound enzyme expressed by neurons and glia, oriented towards extracellular compartment.  Inhibited by valproic acid and vigabatrin (use in epilepsy)
  8. 8. GABA Function  Relieving anxiety.  Improving mood.  Relieving premenstrual syndrome (PMS).  Regulating the release of sex hormones.  Treating attention deficit-hyperactivity disorder (ADHD).  Promoting lean muscle growth.  Burning fat.  Stabilizing blood pressure.  Relieving pain.  lower elevated blood sugar levels in diabetics.
  9. 9. GABA A  Ligand gated ion channel.  Distributed throughout the brain.  It is a heteropentamer, made of five subunits with each subunit containing four α helical membrane spanning.  Ligand binds at the interface between α and β domain.
  10. 10.  There are many different types of GABA A receptors depending on the type of subunit present.  Subunits also called isoforms – alpha(1-6), beta(1-3), gamma(1-3), delta, epsilon, pi, theta and rho.  Different types of GABA A receptors are present in different regions of the brain and at different levels of development.
  11. 11. Allosteric modulation  The site where modulators bind is different from the site of binding of GABA agonist – known as “allosteric” site and the modulator is called “allosteric modulator”. The modulator has no activity of its own.  Positive Allosteric Modulation: ligand binds allosteric site and enhance the action of neurotransmitter. E.g.BZD  Negative Allosteric Modulation: ligand binds to the allosteric site while an agonist is also bound and the channel opens less frequently then when
  12. 12.  GABA A receptors with alpha 4/6 and delta subunit are insensitive to benzodiazepines.  Binds to modulators – naturally occurring neurosteroids, alcohol and some general anesthetics.  Located extrasynaptically. Regulated by extracelullar GABA molecule that has escaped reuptake and enzymatic destruction  Mediate tonic inhibition of postsynaptic neuron  Not sensitive to BZD – no anxiolytic actions of BZD
  13. 13.  GABA A receptor when activated, mediates an increase in the conductance.  Increase in the influx of Cl- ions causing membrane hyperpolarization.  Increase in the threshold for generating action potential. Inhibitory action
  14. 14. GABA-A
  15. 15.  GABA A receptor with alpha 1/2/3, beta, gamma 2/3.  Postsynaptic in location – phasic inhibition. Bursts of inhibition triggered by peak concentration of synaptically released GABA.  Sensitive to BZD – Anxiolytic actions.  Alpha 1 – most important for regulating sleep – target for various sedative hypnotic agents.  Alpha 2/3 most important for regulating anxiety.  Abnormal expression of alpha 2, gamma 2 or delta
  16. 16. GABA B  Differentiated from GABA A by  Insensitive to GABA A antagonist Bicuculline.  Activated by Baclofen  Member of G-protein couples receptor. Dimer of two seven transmembrane spanning subunits.  Located both pre and post-synaptically.  Presynaptically- Activation of presynaptic GABA-B receptors decreases the release of GABA and of different transmitters..  Postsynaptically – Activation of postsynaptic GABA- B receptors modulates the opening of potassium channels, which induces an intracellular potassium
  17. 17. Neuropsychiatric implications I. Anxiety disorders  Amygdala central circuit – amygdala plays central role in the expression of fear and anxiety.  Cortico-Striatal-Thalamo-Cortical (CSTC) loop – linked to worry and obsessions across the spectrum of anxiety disorders.
  18. 18.  GABA is the principal inhibitory neurotransmitter in the brain and serves an important regulatory role in in reducing the activity of many neurons including those in Amygdala and CSTC loop.  GABAergic dysfunction has been associated with anxiety disorders, esp with panic disorder.  Magnetic Resonant Spectroscopy reveals significant reduction in GABA levels in the Basal ganglia.
  19. 19. II. Mood disorders  Magnetic Resonant Spectroscopy reveals significant reduction in both GABA and Glutamate in Prefrontal cortex in Major Depressive Disorder.  Post mortem studies revealed up regulation of the GABA receptors alpha1 and 2 subunits, consistent with a reduction in GABAergic neurotransmission.  Reduced levels of GABA in occipital cortex in episodes of major depressive disorder normalised with effective treatment with SSRIs
  20. 20.  In animal studies – valproate, carbamazapine, lithium and lamotrigine a/w in increase in GABA turnover in brain.  Endocrinal hypothesis: estrogen induces downregulation of GAD resulting in inhibitory action on GABA formation resulting in increased activity of pyramidal cells.
  21. 21. III. Schizophrenia  Corticobrainstem glutamate pathways and NMDA receptor function hypothesis  Descending glutaminergic pathway projects from cortical pyramidal cells to brainstem neurotransmitter centres inclusing raphe for serotonin, VTA and substantia nigra for dopamine and locus ceruleus for norepinephrine.
  22. 22.  Corticostriatal glutamate pathway (CSTC loop)  Descending glutaminergic output from the pyramidal cells in cortex nucleus accumbens in ventral striatum forming first leg of the CSTC loop.  Ascending pathway from thalamus to cortex – return leg of the CSTC loop.  GABA neurons located in the thalamus acts as the sensory filters and prevents too much sensory input from penetrating the thalamus into the cortex.
  23. 23.  Dopamine inhibits GABA in CSTC loop reduces the effectiveness of thalamic filter opposes the excitatory input of the glutamate from corticostriatal glutamate projections.
  24. 24.  Epilepsy  In epilepsy, abnormal electrical discharges are due to hyperexcitable neurons with sustained postsynaptic depolarization.  Decreased GABA inhibition of cortical excitability is one of the proposed mechanism.  Penicillin induced cortical injury causes seizures through decreased GABA inhibition.  BZD and barbiturates reduces seizures by enhancing GABA receptor current and valproate through blockade of GABA catabolism.

×