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38 Cards in this Set
- Front
- Back
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Types of NT's (neurotransmitters) |
Small molecules - biogenic amines (dopamine, norepinephrine, epinephrine, 5-HT [serotonin], histamine), glu, Asp γ-aminobutyric A (GABA), gly, Ach, purines (ATP) Larger & neurohormones - opioids, cannabinoids, substance P, vasopressin, oxytocin, gonadotropin releasing hormone (GnRH), neuropeptide Y, etc. |
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NT receptors |
ionotropic = ligand-gated ion channels (LGIC's) - 4/5 subunits; family heterogeneity -> diversity - can be affected by voltage or desensitized - present both pre- & post-synaptically -> NT release modulation, ΔV - passive, fast-acting metabotropic = G Protein-Coupled Receptors (GPCR's) - act via 2nd messengers (cAMP, Ca2+, DAG, IPs) - slower & long-lasting activity |
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Ionotropic NT R's |
Excitatory - Ach -> nicotinic (sM, n.) - Glutamate -> NMDA, AMPA, Kainate - Adenosine & ATP -> Purinergic R's Inhibitory - GABA -> type A [Cl-, brain] - Glycine [spinal cord] |
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Metabotropic NT R's |
α & β norepinephrine (NE) R's serotonin [5-HT(1,2,4,5,6,7)] R's dopamine (DA) R's muscarinic ACh R's GABA(B) R's L-AP4 glutamate R's ACPD (metabotropic) glutamate R's Cannabinoid R's [CB(1,2)] > 50 receptors for neuromodulatory peptides ATP & adenosine |
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Neuromuscular jxn |
- 1 α motorneuron: Ach -> nAChR (nicotinic ACh R) in a muscle fiber - safety factor ~ 1:1 [pre- -> post-synaptic AP], due to: -- each AP -> large # of ACh vesicles released -- optimization of ACh action at postsynaptic fiber by highly specialized organization |
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Pre-synaptic specializations |
Active zones along axon: - tethered vesicles w/ Ach, adjacent to - VGCC's => Ca driving F (>+100mV) -> binds to - SNARES (synaptotagmin; NSF) -> fusion of vesicles & PM -> exocytosis -> release of NT quantum (~10k ACh molecules) |
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SNARE suppressors |
botulinum toxin (BoTox) --| acidic vesicles in MN's tetanus toxin: retrogradely transmitted from α-MN's --| 2° inhibitory interneurons (IN's) |
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Post-synaptic specializations |
Postsynaptic folds directly aligned w/ presynaptic active zones: - High R densities (10k R's/μm^2) - Basal lamina (in funnel): acetylcholinesterase (AChE) --| ACh Troughs of postsynaptic folds: - hi density of VGNC's -> AP's |
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nAChR (Nicotinic ACh R) |
- permeable to both Na > K (some also to Ca++) - E(nAChR) >= 0 mV = V(rev) (when open) - pentameric proteins - fast excitatory PSP in peripheral n.'s & NMJ's - active in presynaptic modulation in CNS |
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Mean quantal content |
m = n*p mean amount of NT released = # of vesicles * probability of release |
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Lambert-Eaton Syndrome (LES) |
= autoimmune disorder where Ab's x presynaptic VGCC -> defective synaptic transmission => sM weakness, fatigue - treatment: --| VGKC |
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R Desensitization |
Agonist bound for prolonged t -> conformation -> desensitization (stops firing) Organophosphates (OPs) = pesticides/weapons (sarin) --| AChE -> ACh overload -> desensitization -> insufficient neuromuscular signaling -> weakness, resp. failure, death -> treatment: 2-PAM (Pralodoxime) |
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Myasthenia Gravis (MG) |
= autoimmune disorder: Ab x nAChR
-> loss of nAChRs, simplified synaptic folds, widened synaptic space -> insufficient neuromuscular transmission -> decreased safety factor => weakness (myasthenic snarl) - AChases used for diagnosis & therapy |
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Patch Clamp Technique |
Single channel AChR activity recording -> single channel currents -> mini's |
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CNS post-synaptic response |
Relatively small: ~50 R's -> 0.5-1.0 mV - no one signal is important -> summation based on efficacy, etc. => plasticity |
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Excitatory vs. Inhibitory synapses |
Fast excitatory: spines Fast inhibitory: proximal to soma (major dendritic shafts & cell body) |
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NT activity control |
Diffusion Reuptake Enzymatic degradation |
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AMPA R's |
Glutamate -> major mammalian CNS excitation: - cation-selective (Na/K; ↓Ca); V(rev) = 0mV -> excitatory - fxnal diversity: 4 subunit genes (GluR2), alternative splicint, RNA editing - GluR2 editing failure -> ↑Ca permeability -> ALS - localized to dendritic spines |
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NMDA R's |
Gutamate -> - cation-selective (Na/K; ↑Ca); V(rev) > 0mV -> excitatory - Mg --| @ hyperpolarized & resting potentials - important in LTP & LTD (coincidence detectors) - role in excitatory AA toxicity - localized to dendritic spines |
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Purinergic R's |
-> ATP/adenosine - non-selective excitatory cation channels - role in pain & mechanosensory transduction in PNS - caffeine/theophylline --| |
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GABA(A) R's |
- primarily Cl- [E(rev) = -65/-75 mV] & HCO3- -> inhibitory, mostly in brain |
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Glycine R's |
- Cl- [E(rev) = -65/-75 mV] -> inhibitory in spinal cord of adult |
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Subunit heterogeneity |
- cell-specific - region-specific - developmentally regulated - diversity within a cell -> variety of fxnal & pharmacological characteristics |
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Allosteric regulation of ion channels |
- ability of compounds to change channel fxn/effect by binding to specific sites (not as ligands) - affect open P, desensitization, conduction period, etc. - benzodiazepines, barbiturates, anesthetics; neurosteroids; ethanol, anabolic steroids - effect depends on subunit composition |
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Benzodiazepines |
- bind to α (not α6) & γ subunits of GABA R - in presence of GABA -> enhance its efficacy => greater inhibition - endozepines? - prevent thalamus hyperexcitability (X seizures) |
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Extrasynaptic R's |
- low [GABA] present in ECF -> tonic inhibition via δ subunit, high affinity for GABA -> tonic current - enhanced by amnesic drugs: propofol, isofluorane |
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Developmental changes in Cl- gradients |
GABA: - inhibition in adult (Cl- in) - excitatory in neonates (Cl- out): E(rev) = -36mV -- due to NKCC1 -> ↑ IC [Cl-] - later: ↓NKCC1, ↑KCC2 -> Cl- outflow => ↓ IC [Cl-] - important for development & differentiation - recapitulted in neuronal insult in adults |
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Changes in presynaptic efficacy |
Facilitation - AP's in rapid succession: - residual Ca++ => ↑ NT vesicles released / AP Synaptic Depression - prolonged, ↑ freq. activity - vesicles depleted => ↓ NT vesicles released / AP LTP (Long-Term Potentiation) |
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Changes in post-synaptic efficacy |
Temporal summation - 2 events (1 input) in rapid succession add up - depends on time constant, τ or post-synaptic membrane Spatial summation - 2 adjacent events (separate inputs) sum up - depends on λ, length constant or the PS memb. |
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Presynaptic modulation by ionotropic R's |
Ex.: nAChR - on presynaptic n. terminals - Na influx -> depolarization, Ca permeability -> augments presynaptic NT release - promotes release of variety of NT's (-> nicotine addition) |
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Metabotropic NT R's (GPCR's) - examples |
α and β norepinephrine (NE) R's serotonin [5-HT(1,2,4)] R's dopamine (DA) R's muscarinic ACh R's histamine R's purinergic R's GABA(B) R's Metabotropic glutamate R's Cannabinoid R's [CB(1,2)] > 50 receptors for neuromodulatory peptides |
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Metabotropic NT R's (GPCR's) |
NT -> GPCR activation -> 2nd messengers - amplification, divergence; self-limiting (auto GTPase) - 6 major classes (by IC signalling pwy's, regions, cell types, pharmacological profiles) |
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Serotonin (5-HT) R's |
- widely expressed throughout CNS: serotonergic neurons in the dorsal raphe -> almost global projections - presynaptic modification of almost all NT's -> implicated in various fxn's, Alzheimer's |
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Cannabinoid R [CB(1)] |
<- endocannabinoids, THC - localized to presynaptic terminals -> NT release modulation in mesolimbic reward system: -- NAc: DA neurons -- VTA: GABAergic interneurons -> G(i/o) --| cAMP (AC) ->> ↓ GABA release -> ↑ DA |
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Glia |
neurons:glia ~ 1:1 - [ion] & [NT] regulation - required for myelination, neural migration, responders to injury - Ca waves -> AP spread in e-coupled astrocytes -> NT-modulator release (D-serine, ATP, glu) |
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Glial cell types |
- oligodendrocytes - myelinating glia - astrocytes - ion & metabolic homeostasis; regulate n. # & fxn's, blood flow, synapses, complement cascade -> pruning - NG2 glia - synaptic remodeling - microglia - sensing, phagocytosis & defense, complement R's |
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Schizophrenia |
- loss of grey matter & synapses - C4A localization to synapses -> C3 -> phagocytosis by microglia |
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Electrical transmission |
- gap jxn channels = connexons (each made of 6 connexins) -> passage of small molecules - found in development & neurons that fire synchronously - permeability regulated by 2nd messengers - implicated in congenital deafness |
