BIOL 2P94 Lecture Notes - Dlg4, Transamination, Neuroprotection

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Outline of Lectures 17 (02-21 D; Snyder) and 21 (02-24 C; Snyder)
Amino Acids
I. GABA: the principal inhibitory neurotransmitter
- Synthesis: decarboxylation of Glu (nerve terminal) or by transamination (in mito)
- GABA inactivated by reuptake by ensheathing glia
- GABA-A receptor
- Ionotropic Cl channel (hyperpolarizing inhibition)
- Multiple binding sites particularly benzodiapine site (Valium is agonist, allosteric with GABA)
and barbituate (target of sedatives, and perhaps alcohol)
- Found in the cortex and inhibited by bicuculline (compare to Gly)
- GABA-B receptor: metabotropic autoreceptor, inhibitory via opening K channels or Ca
conductance, drug target of Baclofen
II. Glycine: another inhibitory neurotransmitter
- Although Gly is found in nerve terminals throughout CNS, Gly receptors are found primarily in
spinal cord and are inhibited by strychnine and not bicuculline (see GABA-A)
- Gly is inactivated by reuptake
- Gly found in interneurons that inhibit motoneurons; drug mimics are good muscle relaxants
III. Glutamate: principal nxt in the brain
- Synthesis: from Gln or transamination, the nxt pool is unclear; highly abundant aa
- Glu acts on presyn and postsyn, inactivated by reuptake by glia and neurons
- Non-NMDA receptors
- Ionotropic, lets Na in and K out, depolarizing and excitatory
- NMDA receptors
- Ionotropic, lets Na and Ca in and K out
- Ca activates intracellular signaling, might be important in learning and memory
- Multiple binding sites, e.g. Mg++ and PCP
- Metabotropic receptors: GPCR linked to IP3 or cAMP, both presyn and postsyn
- Scaffolding proteins play an important role in signal transduction, particularly PSD95 for
NMDA receptors (indirectly linked to NOS)
IV. D-serine
- Synthesis: L-serine D-serine by serine racemase
- D-serine is released by astrocytes in response to Glu nxt
- D-serine acts on the “glycine” site of the NMDA receptor, and is required for Glu nxt activity
(perhaps a protective mechanism)
V. Nitric oxide (NO)
- Synthesis: Arg NO + citrulline by NO synthase (NOS)
- NO is a “gaseous” nxt in the brain, also relaxes blood vessels, and in macrophage killing
- NO results in cGMP ( phosphodiesterase inhibitors have similar effects to NO) and can
directly nitrosylate NMDA
- NOS is highly regulated by serine protein kinases and PSD95 (a link between NMDA and NOS)
- NO might mediate behavioral suppression (NOS knockout mice are hyperaggresive and
hypersexual), is an nxt in the autonomic NS (e.g. peristalsis, penile erection), and elicits damage
during stroke
VI. Carbon monoxide (CO)
- Synthesis: Heme CO + biliverdin by heme oxygenase (2 forms: HO1, HO2)
- HO1: inducible, found in spleen
- HO2: not inducible, found in neurons (particularly gut, with NO), acts through cGMP
- Bilirubin (made from biliverdin) is a potent antioxidant and neuro-protectant
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