BRAIN METABOLISM

 Nervous system – communication network between environment and body; Brain – command center, requires plenty of energy, has billions of neurons
 Brain macromolecules – complex and specialized lipids for integrity rather than metabolism
 Proteins – rapid turnover rate; Lipid – 50% of neurons’ dry weight, ¾ of myelin, comprises of phospholipids, glycolipids, sphingolipids

Neuron
 Highly specialized cell of NS
 ATP from glucose metabolism maintains negative resting potential (-70 mV) thanks to Na-K ATPase
 Membrane depolarization due to voltage-gated ion channels
 Surrounded by Schwann cells – forms myelin sheath for saltatory conduction of action potentials

Myelin sheath
 50-100 stacks of specialized plasma membrane wrapped around axons
 Composition: myelin associated protein (MAG – stabilizes glia-axon junction), myelin basic protein, proteolipid, and phosphohydrolase
 Interrupted every mm along axon by nodes of Ranvier –axonal membrane meets ECF, high Na channel density, for saltatory conduction

Multiple Sclerosis
 Neurologic disease, demyelination of axons = slower AP conduction
 May be autoimmune or infectious – antibodies react with myelin proteins or due to protease secretion
 Predisposing factors: lipid /FA metabolism disturbance, ↓ PUFA & EFA, disturbance in FA elongation, 1° increased activation of PLA1

Energy Metabolism
 Brain is well-vascularized, needed for constant energy production
 Consumes 20% O2 and 60% glucose at rest, most energy is used in Na-K ATPase
 Normally uses glucose (120g/day or 15% of total energy), uses ketone bodies during prolonged starvation (but still needs glucose)
 Fatty acids unusable (due to binding with albumin), amino acids unusable (neurons incapable of gluconeogenesis)
 Amino Acid Metabolism
o Brain intracellular AA levels ↑ than liver, AAs used for neurotransmitter (NT) production: Glu, Asp (2 most abundant), Gly and GABA
o Glu and Asp transaminated to oxoglutarate and Oxaloacetate; GABA from decarboxylation of Glu

Resting and Action Potential

 Na-K ATPase constantly pumos Na out for K ions = large differences in cellular and ECF concentrations
 K channels open even while resting while Na and Cl are closed  constant K efflux to ECF = negative resting potential (-60mV) = K ions make greatest contribution to membrane conductivity
 AP: Na channels open  Na influx = charge reversal  voltage-gated K channels open  K ions flow out = charge returns (overshoot possible)  return to resting state

Synapse
 Junction at which neurons pass signals to other neurons, muscles or glands
 Axodendritic, axosomatic or axoaxonic connections
o Electrical – rapid, 20 A synaptic cleft gap, triggers AP on postsynaptic membrane directly
o Chemical – slower, 200 A gap, neurotransmitter release  binds to postsynaptic membrane

Cholinergic Synapse
 uses Ach, with either nicotinic or muscarinic receptors
 Transmission: AP arrives  voltage-gated Ca channels open  Ca influx  exocytosis of vesicles  Ach diffuses into synaptic cleft  binds with nicotinic AchR  AP generated (Na in, K out)
  2 Alpha / Beta / Gamma / Delta glycoprotein subunits in quasi-fivefold symmetry, Ach binds with alpha
 water-filled central gated ion channel
 2 Ach binds = ion channel opens = Na in, K out for 1-2msec  Ach dissociates
 Ach antagonists – prevent channel opening
o D-tubocurarine – arrow-poison curare, medically useful paralytic agent
Nicotinic o Atropine – blocks Ach @ muscarinic receptor
o Botulinus toxin – from Clostridium botulinum, food poisoning, inhibits Ach release
 Ach agonists – keep channel open
o Decamethonium – binds to nAchR = permanent depolarization
o Nicotine – locks channel open
o Succinyl choline – slow hydrolysis by acetylcholinesterase  persitent depolarization, as muscle relaxant, short lived

Muscarinic  Ach binds activating G protein transducing  active Gα opens K channel  long-lived hyperpolarization of membrane
 For slow cardiac muscle contraction
Acetylcholine metabolism
 Synthesis: acetyl group from acetyl CoA + choline with choline acetyltransferase enzyme
 Packaging/Storage: 1K-10K molecules in synaptic vesicles
 Release: Ca triggers exocytosis from synaptic vesicles
 Degradation: hydrolyzed by acetylcholesterase into choline and acetate
 Reuptake: choline and acetate taken up by presynaptic neuron, recycled

Acetylcholinesterase
 Serine esterase that degrades Ach before arrival of a next impulse, produces acetate and choline for reuptake
 Anti-acetylcholinesterases via blocking serine residue in active center
o Diisopropyl fluorophosphates / Parathion – irreversible inhibits acetylcholinesterase = permanent depolarization
o Sarin – in military nerve gas, cholinergic blockade, causes suffocation
o Physostigmine – plant alkaloid, prevents Ach binding

 Competitively inhibited by curare (arrow poison) – blocks Ach binding site

Neurotransmitters (NT) – produced by neurons, stored in synapses, released into synaptic cleft, binds specifically to postsynaptic membrane receptors, triggers ion flux

Direct Typical, presynaptic AP depolarizes synaptic terminal  voltage-gated Ca channels open  Ca influx  neurotransmitter release
Indirect Via 2° messengers, NT activates G protein in postsynaptic membrane releasing Gs (stimulatory) or Gi (inhibitory)  enzyme activation or ion channel opening
Excitatory Produces localized change in postsynaptic neuron, creates AP, Ach, Glutamate, catecholamines, serotonin
Inhibitory Blocks AP, opens Cl channels to hyperpolarize neuron, GABA, Glycine

Neurotransmitters Short-lived, released into synaptic cells, short range effect

Neurohormones Longer-lived, released to blood, long range effect, modifies how neurons respond to neurotransmitters

Chemical Classification of NTs

Type NT Notes Synthesis / Degradation Modulators
in neuromuscular junction,
Ach
nicotinic (fast) and muscarinic (slow) receptors
 In astrocytes, becomes Glu
Glutamine
or GABA
most widespread excitatory, at least 4 postsynaptic receptors: (NMDA [Na, K,
Amino Acids Glutamate
Ca], AMPA [Na, K], kainite)
Glycine inhibitory blocked by strychnine
Aspartate CAC intermediate
most widespread inhibitory, removed from synapses via uptake, from glutamate + Glu inhibited by opiates,
GABA
GABA-A (Cl) and GABA-B (K) receptors decarboxylase alcohol prolongs conductance
NE, E, DOPA, from tyrosine, degraded by
Biogenic amines (from dopamine COMT and MAO
AA decarboxylation) Dopamine inhibited by cocaine
90% in GI, for temp. regulation, mood, impulsivity, cognition & sleep, from 5-OH tryptophan,
Serotinin
7 receptors (5-HT-17-, G proteins + AC or PLC) degraded by MAO
Histamine from histidine
Purine derivates ATP, ADP, AMP Adenosine derivatives
bind to opiate receptors in brain, natural analgesics, not reuptaken, has cyclic
Peptides glutamate
Substance P Inhibitory, excitatory if inhibits inhibitory neuron
B-endorphin 31 AA, most potent from POMC
Met-/Leu-
widely distributed in brain 5 AA from proekpehalin
Endorphins enkephalin
4 peptides from
Dysnorphin
prodysnorphin (257 AA)