Neurotransmitters

Question 1

describe the 3 different different types of neuronal chemical synapses

Answer 1

1. axodendritic synapses excite the postsynaptic neuron, increasing the likelihood of action potentials
2. axosomatic synapses inhibit the postsynaptic neuron
3. axoaxonic synapses inhibit the ability of action potentials to provoke release of trasmitter

Question 2

describe tripartite synpases

Answer 2

• tripartite synapses exist among presynaptic and postsynaptic neurons and astrocytic endfeet
  
  • astrocytes take up transmitters released by nerons (glutamate) and release others (glutamine) for absorption by neurons

Question 3

describe the synthesis of small-molecule transmitters

Answer 3

• small molecule transmitters undergo cytosolic synthesis
• they are typically loaded into clear vesicles for tethering to the cytoskeleton near the active zones in anticipation of release

Question 4

describe the synthesis of neuropeptide (high molecular weight)

Answer 4

• neuropeptides arise from propeptides which are synthesized in the soma and undergo anterograde axonal transport
• the propeptides are cleaved to yield multiple peptide neurotransmitters that remain in the large dense-core vesicles pending exocytosis
  
  • the dense core vesicles are stored farther from the active zone than the clear vesicles which contain small-molecule transmitters
• an example is opioid peptides

Question 5

describe the synthesis of nitric oxide

Answer 5

• NO arises from the interaction of nitric oxide synthase (NOS) and l-arginine
• synthesis of NO occurs on-demand since it is not stored

Question 6

describe the loading of vesicles

Answer 6

• filling of synaptic vesicles may involve the movement of H+ ions
  
  • vesicular membranes may express antiports that exchange dopamine (DA+) for H+

Question 7

describe the process of exocytosis of neurotransmitters

Answer 7

• synapsin tethers vesicles to the cytoskeleton
• phosphorylation of synapsin by Ca-calmodulin-dependent protein kinase liberates vesicles from the cytoskeleton
• Rab proteins facilitate movement of vesicles towards the active zones
• docking of the vesicles with nerve terminal membrane depends upon binding of SNARE membrane proteins
  
  • vesicular membranes have v-SNARE proteins and the nerve membrane has t-SNARE proteins
• after docking, the vesicular membrane protein synaptophysin may form the fusion pore in the nerve terminal membrane, allowing release of transmitter

Question 8

describe the role of calcium in exocytosis

Answer 8

• Ca++ liberates/untethers vesicles by promoting phosphorylation of synapsin
• Ca++ facilitates the opening of the inserted fusion protein allowing transmitters to leave the vesicle and enter the synaptic cleft

Question 9

describe the membrane retrieval by endocytosis following exocytosis of small clear vesicles

Answer 9

• the membranes of small clear vesicles undergo local recycling
• recylcling relies on endocytosis mediated by the protein clathrin, which coats the vesicles
  
  • once internalized, the vesicles lose their coats and fuse with the endosome which forms new vesicles for refilling with transmitter

Question 10

describe the membrane retrieval by endocytosis of dense core vesicles

Answer 10

• the empty dense core vesicles after exocytosis are transported retrogradely to the soma for refilling

Question 11

describe ionotropic receptors and name 3 examples

Answer 11

• transmitters diffuse across the synaptic cleft and bind to receptors
• some receptors (ionotropic) change conformation when binding an agonist, either opening or closing a central ion-passing pore
• the change in ionic conductance shifts the membrane potential
• examples:
  • nicotinic AChR
  • GABAA receptor
  • NMDA receptor for glutamate

Question 12

describe metabotropic receptors and name 2 examples

Answer 12

• metabotropic receptors act via G-proteins, which influence enzymes and therefore second messengers
• metabotropic muscarinic AChR and norepinephrine receptors exemplify transmitter-induced intracellular signaling cascades, which may involve activated kinases, liberated calcium and phosphorylation of channels for K, Ca, or Cl

Question 13

describe the synthesis and removal of ACh

Answer 13

• glucose enters cell via facilitated diffusion
• cytoplasmic glycolysis synthesizes pyruvate
• pyruvate enters mitochondria
  
  • donates acetyl group to coenzyme-A
  • acetyl coenzyme-A returns to cytoplasm
• choline retrieved from the synpase interacts with the acetyl-CoA in presence of ACh transferase to yield ACh
• ACh enters vesicles
• ACh esterase in the synapse hydrolyzes ACh and the resultant choline is taken up for reuse

Question 14

describe the central cholinergic nuclei and projections

Answer 14

• cholinergic nuerons of the rostral pons project to the brainstem, thalamus, hypothalamus, cerebellum, basal ganglia and other cholinergic cells of the basal forebrain
• cholinergic neurons of the basal forebrain project to the cortex, hippocampus and amygdala
• pregang. autonomic neurons dwell just medial to the sulcus limitans in the brainstem and select levels of the thoracic, lumbar and sacral spinal cord
  
  • typically follow cranial nerves or central spinal nerves to release ACh onto either postgang. neurons or adrenal chromaffin cells
• lower motor neurons give rise to axons that exit the central nervous system en route to somatic muscle

Question 15

describe peripheral cholinergic neurons

Answer 15

• postgang. neurons innervate visceral targets
  
  • all PS postgang. and some symp. PG neurons also release ACh

Question 16

describe how the Krebs cycle is involved in the synthesis of glutamate

Answer 16

• Krebs cycle
  
  • glucose enters neuron by facilitated diffusion
  • intracellular glucose metabolized via Krebs cycle
  • alpha-oxoglutarate transaminase yields glutamate

Question 17

describe the glutamate recycling

Answer 17

• terminal and astrocytic glutamate transporters take up extracellular glutamate
• glutamine synthesase metabolizes glutamate to form glutamine in astrocytes
• glutamine exits astrocytes and enters neurons through glutamine transporters
• intraneuronal glutaminase converts glutamine to glutamate for reloading into vesicles
• glutamate taken up by neuronal terminals is also subject to vesicular reloading

Question 18

name 3 ionotropic glutamate receptors

Answer 18

• AMPA/quisqualate
  
  • agonists provoke the influx of Na and the efflux of K
• Kainate
  
  • agonists provoke the influx of Na and the efflux of K
• NMDA
  
  • agonists open a central pore, provided that glycine also occupies a strychnine-insensitive binding site
  • with sufficient depolarization of the membrane, Mg exits thus permitting the influx of Ca and Na and the efflux of K
  • NMDA receptor-dependent ionic fluxes contribute little to changes in membrane potential but promote Ca-dependent processes (enzyme activity)

Question 19

name the 3 groups of metabotropic glutamate receptors

Answer 19

• I
  
  • 1 and 5
  • typically postsynaptic and excitatory
• II
  
  • 2 and 3
  • typically presynaptic and inhibitory
• III
  
  • 4 and 6-8
  • typically presynaptic and inhibitory

Question 20

describe the synthesis and removal of GABA

Answer 20

• glutaminase converts glutamine to glutamate
• glutamic acid decarboxylase converts glutamate to GABA
• GABA is loaded into vesicles
• after release, GABA transporters take up GABA for reuse
• glia take up GABA where GABA transaminase degrades GABA to form glutamate
• glutamine synthetase then converts glutamate to glutamine
• glutamine may be returned to neurons for re-synthesis of glutamate

Question 21

describe GABA receptors

Answer 21

• GABA receptors are ionotropic and permeable to Cl-
• as the equilibrium potential for Cl- is close to the normal resting membrane potential, GABA actign rhough GABA receptors, tends to limit excitability of neurons by holding membrane potentials near resting values
• GABA receptors have allosteric binding sites for barbituates and benzodiazepines
  
  • with the binding of barbs/benzos, GABA tends to trigger larger Cl- currents

Question 22

describe the synthesis and removal of glycine

Answer 22

• glycolysis of glucose yields 3-phosphoglycerate and subsequently serine
• serine transhydroxymethylase folate-dependently converts serine to glycine
• membrane-spanning transporters take up synaptic glycine

Question 23

describe the nuclei and projections of glycine

Answer 23

• glycinergic neurons tend to be small, exerting local inhibitory actions in the retina and the gray matter of the brainstem and spinal cord

Question 24

describe glycine receptors

Answer 24

• ionotropic glycine receptors bear structural and functional similarities to GABA receptors, likewise acting as ligand-gated Cl- channels
• blocked by strychnine

Question 25

describe the synthesis and removal of dopamine

Answer 25

• tyrosine is actively transported into catecholaminergic neurons
• tyrosine hydroxylase converts tyrosine to dopa
• dopa decarboxylase converts dopa to dopamine
• dopamine is loaded into vesicles for release
• reuptake-1 actively transports dopamine into the presynaptic neuron
  
  • some dopemaine is reloaded into vesicles
  • remaining dopamine is metabolized by MOA
• reuptake-2 actively transports dopamine into postsynaptic cell for metabolism by COMT
• remaining synaptic dopamine diffuses and is absorbed by blood for peripheral metabolism

Question 26

describe the nuclei and projections of dopamine

Answer 26

• the substania nigra pars compacta projects via the nigrostriatal pathway to the caudate and putamen to regulate motor fxn
• the ventral tegmental area, situated medial to the substantia nigra, projects to:
  
  • prefrontal cortex
  • nucleus accumbens and limbic structures
• the hypothalamic arcuate nucleus projects to:
  
  • hypothalamic median eminence for dumping of dopamine into hypophyseal portal system to suppress release of prolactin

Question 27

describe the 2 groups of metabotropic dopamine receptors

Answer 27

all metabotropic

• D1-like (1 and 5) increase production of cAMP
• D2-like (2,3,4) decrease production of cAMP

Question 28

describe the synthesis of norepinephrine

Answer 28

• dopamine is loaded into vesicles (like dopamine) with dopamine-B-hydroxylase which converts dopamine to norepi.

Question 29

describe the nuclei and projections of norepi.

Answer 29

• the rostral pontine locus coerueleus projects to the diencephalon, limbic system, cerebral lobes and the cerebellum
• other clusters of pontomedullary noradrenergic nuclei project to the nucleus of the solitary tract (NTS) and spinal targets

Question 30

describe the synthesis of epinephrine

Answer 30

• norepi. leaks from vesicles into the cytoplasm
• cytoplasmic norepi. interacts with PNMT to yield epinephrine
• epinephrine is reloaded into vesicles

Question 31

describe the synthesis and removal of serotonin (indolamine)

Answer 31

• tryptophan hydroxylase converts cytoplasmic tryptophan to 5-hydroxytryptophan
• amino acid decarboxylase converts 5-hydroxytryptophan to 5-HT (hydroxytryptamine)
• 5-HT undergoes active transport into vesicles for release
• synaptic 5-HT can undergo reuptake of metabolism by MAO to 5-HIA
  
  • aldehyde dehydrogenase then converts 5-HIA to 5-hydroxy-indoleacetic (5-HIAA) acid for urinary excretion

Question 32

describe the synthesis and removal of histamine

Answer 32

• histidine is actively transported into the brain
• histidine decarboxylase converts histidine to histamine
• histamine is metabolized to organic aldehydes and acids by histamine methyltransferase and diamine oxidase

Question 33

describe the synthesis of beta-endorphin

Answer 33

• Pre-proopiomelanocortin in pituitary and hypothalamus
• Transported to periaqueductal grey and noradrenergic nuclei
• Proteolytic cleaving yields beta-endophin, among other peptides
  
  • Binds to Mu opioid receptors

Question 35

describe the nuclei, synthesis and projection of enkephalin

Answer 35

• Pre-proenkephalin in local spinal and caudal bulbar neurons
• Proteolysis yields leu- and met-enkephalin
  
  • Bind to delta opioid receptors