Neurochemistry+II

=**Neurochemistry II**=


 * 12. Discuss the metabolism of GABA: synthesis, degradation and the GABA shunt.**

Gamma-amino butyric acid (GABA) is an amino acid synthesized from glutamate. Glutamate is decarboxylated by glutamic acid decatboxylase (GAD) to form GABA. It is degraded by GABA transaminase (GABA-T) to succinic semialdehyde which is further broken down by succinic semialdehyde dehydrogenase (SSADH) to succinic acid. The amino group transaminated by GABA-T is moved to alpha-ketoglutarate to form glutamate.

The synthesis of GABA requires a neuron to pull alpha-ketoglutarate out of its TCA cycle metabolism via the GABA shunt. This costs the neuron one GTP that could be converted to ATP. When succinic acid re-enters the TCA cycle after GABA degernation, NAD is reduced to NADH+H+.

TCA cycle: 3 ATP from NADH+H+ and 1 GTP (convertible to ATP) GABA shunt: 3 ATP from NADH+H+ only.

Thus, synthesis of GABA is energetically expensive.


 * 13. Describe the types of the GABA receptors and the mechanism of action of the benzodiazepines.**

GABA//a// receptors are ionotropic and acts to open Cl- channels which enter and hyperpolarize the cell. The subunits of GABAa receptor form a Cl- channel. Benzodiazepines such as valium and Librium regulate the GABAa receptor by binding at the regulatory site; they are not GABA agonists but are able to enhance the binding of GABA to its receptor.

GABA//b// receptors are metabotropic receptors coupled K+ and Ca2+ channels.

GABA//c// receptors are ligand-gated Cl- but relatively slow kinetics and poor sensitivity compared to GABA//a// to certain antagonists like bicuculline and regulators like benzodiazepines and barbiturate anesthetics that affect the A and B receptor subtypes.

Blockage of GABA receptors can result in seizures or convulsions.


 * 14. Summarize the evidence that glycine is a neurotransmitter in the spinal cord.**

Glycine is synthesized from serine and is most notably found in the spinal cord. Glycine receptors are like GABA receptors in that it affects Cl- permeability but is distinguished pharmacologically because it is blocked by strychnine (GABA//a// receptors are blocked by bicuculline). Glycine is thought to be an inhibitory neurotransmitter in the spinal cord because it is found in presynaptic nerve endings, and it mimics endogenous neurotransmitter in that is released from nerve terminals in response to stimulation.


 * 15. Describe the role of glutamate as an excitatory neurotransmitter in the CNS.**

Glutamate is a powerful excitatory neurotransmitter in the CNS. Its actions are mediated by AMPA/Kainic acid receptors, NMDA receptors, and metabotropic receptors. AMPA/Kainic acid receptors are ionotrophic and increase Na+ and K+ conductance. Metabotropic glutamate receptors are //G//q protein coupled receptors that increase the activity of phospholipase C.

NMDA receptors are special glutamate receptors. They are also ionotrophic like AMPA receptors but they increase conductance of Ca2+, Na+ and K+. However, NMDA receptors do not open in response to binding glutamate or its agonists because it is blocked by Mg2+ which acts in a voltage-gated manner. That is, in order for NDMA receptors to open, it must not only bind 2 glutamate molecules at its receptor sites, but the postsynaptic terminal must also be depolarized (usually by AMPA receptors) to expel the Mg2+ to expose its ion channel.


 * 16. Discuss the involvement of NMDA receptors in long-term potentiation (LTP).**

Activation of the NMDA receptor is essential for long-term potentiation (LTP). LTP is a synaptic mechanism involved in memory formation and is best characterized in the hippocampus. When NMDA is activated, Ca2+ enters the post synaptic cell and several Ca2+ dependent processes (via CaMK) produce long-term changes in the efficiency of the synapse. Changes can include increasing the number of AMPA receptors in the postsynaptic membrane, and phsophorylation/activation of transcription factors like CREB to regulate gene transcription and increase synthesis of proteins that modify synaptic structure.


 * 17. Distinguish the action of peptides in the CNS from the more classic forms of neuroendocrine regulation: neurosecretion and releasing factors.**

There are two classic ways in which peptides have been shown to interact with the central nervous system: neurosecretion and releasing factors.

__Neurosecretion__ A neuronal cell produces a peptide secretory product and stores it in its presynatpic terminals in a vesicle. When stimulated, the protein product is released from the vesicle analogous to neurotransmitter release. However, unlike neurotransmitters, the releases substance is delivered into the blood stream.

Classically, vasopressin and oxytocin are released from the posterior pituitary via neurosecretion. They are produced in the nuclei of the hypothalamus, transported down axons and stored in the axon terminals of the posterior pituitary. When hypothalamic neurons are stimulated by synaptic inputs, the nerve impulse travels down axons and causes vasopressin or oxytocin release.

__Releasing Factors__ Cells of the anterior pituitary release their hormones in response to regulatory substances (all peptides, except one) synthesized in the hypothalamus and stored in the presynaptic terminals of these neurons. When stimulated, they secrete the releasing factors into the portal system between the hypothalamus and the anterior pituitary. The factors are carried to the anterior pituitary to regulate the release of pituitary hormones and can be inhibitory or stimulatory.


 * 18. Characterize substance P and methionine-enkephalin and provide evidence that they act as neurotransmitters.**

Classic neurotransmitters are synthesized and stored in the presynaptic terminal. Peptide neurotransmitters like substance P and methionine-enkephalin are synthesized in the neuronal cell body, processed, and transported to the presynaptic terminal for vesicular storage/release.

Substance P has acetylcholine-like effects in smooth muscle contraction. It is found in highest concentration in the spinal cord, trigeminal nerve nucleus,and substantia nigra – areas involved in the regulation of pain.

Evidence of substance P’s activity as a neurotransmitter comes from its release by C fibers in the dorsal horn of the spinal cord. C fibers are small diameter afferents in peripheral nerves that convey information about pain and temperature. Substance P is a sensory neurotransmitter in the spinal cord, where its release can be inhibited by opioid peptides released from spinal cord interneurons, resulting in the suppression of pain. Ligation studies and exogenous application to spinal motor neurons confirm substance P as a neurotransmitter.

Methionine-enkephalin may serve as a neuromodulator in the spinal cord, inhibiting release of substance P from primary sensory afferents. Enkephalin-containing interneuron exerts its effects by synapsing directy onto the presynatic terminals of the substance P cell.


 * 19. Determine the precursor/product relationships that exist between pro-opiomelanocortin (POMC), proenkephalin A and the opiate peptides.**

POMC is a precursor of beta-endorphin and other active peptides in the pituitary gland and the brain. Processing of POMC is tissue-specific and regulated proteolysis occurs after synthesis of POMC protein at cleavage sites specified by basic amino acids.

POMC is broken down into ACTH and beta-lipotropin. Beta-lipotropin is further cleaved to form gamma-lipotrophin and beta-endorphin.

Beta-endorphin is the most potent opiate when given //in vivo//, probably reflectingthe resistance of this peptide to breakdown compared to enkephalins. Beta-endorphin normal functions in control of affective state and neuronal sensitivity, as well as neuroendocrine regulation.

Although the first 5 amino acids of beta-endorphin are methionine-enkephalin, there is no precursor-product relationship because there is no cleavage signal at the end of methionine-enkephalin in beta-endorphin. Moreover, distributions of methionine-enkephalin and beta-endorphin in the brain differ with the former correlated with pain-related areas and the latter concentrated in the hypothalamus. There is no leucine-enkephalin sequence found in beta-endorphin or POMC.

Rather, the two enkephalins are formed from pre-proenkephalin A which is cleaved to proenkephain A and further cleaved into methionine-enkephalin and leucine-enkephalin. Methionine-enkephalin and leucine-enkephalin correlate best with inhibition of pain. Potency of these two forms depends on opioid receptor subtypes (mu, delta, or kappa). All three opioid receptor subtypes are metabotropic G-protein coupled and function by inhibiting adenylyl cyclase activity, increaing hyperpolarization by increasing K+ channels conductance and decreasing Ca2+ channel conductance.


 * 20. Discuss the major diseases associated with neurotransmitters.**


 * **Disease** || **Neurotransmitter Dysfunction** ||
 * Parkinson’s disease || Loss of dopaminergic cells in the nigral-striatal system ||
 * Schizophrenia || Overactivity of dopaminergic cells in the mesolimbic and mesocortical systems ||
 * Alzheimer’s disease || Loss of cholinergic cells of the nucleus basalis ||
 * Huntington’s disease (chorea) || Loss of GABA-ergic and cholinergic cells of the striatum ||
 * Myasthenia gravis || Autoimmune response directed against acetylcholine receptor in the neuromuscular junction (NMJ) ||