Neuronal Function (1) Flashcards
In biology what is current associated with? Abbreviations and measurement?
movement of Na or K, I, measured in amps or coulombs/sec
How is voltage or potential described biologically?
strength of an electrical field, potential across a membrane (capacitor), measured at one point (inside the cell) with respect to another (outside the cell)
What is conductance and how is it measured?
g, reciprocal of resistance, ease of current flow
What is capacitance and how is it measured?
in Farrads (C), capacity of a thin sheet of material (cell membrane), to store charges of opposite sign on its surfaces
What is diffusion potential?
accumulation of a positive charge on the right and negative on the left of the membrane causing a voltage potential
How do you calculate the diffusion potential?
61mV log10 [ion]out/[ion]in; at 37 degrees
What maintains the concentration gradients of Na and K?
Na/K ATPase, 3 Na and 2K; 25-40% of metabolic activity of the brain
What are the major extracellular anions?
Cl and HCO3
What are the major intracellular anions?
Cl, phosphate, and proteins
What sets the limits of attainable membrane potentials?
permeability to Na and K
What is the membrane potential of most neurons?
-70mV, which is closer than Ek than Ena
What is depolarization?
hypopolarization; membrane potential is less negative than resting membrane potential
What is hyperpolarization?
aka repolarization; membrane potential is more negative
What are the two important properties of ion channels?
selectivity- size of pore and arrangement of charges allow certain ions to pass more readily; and gating- gates regulate diffusion of ions through pore, can be opened or closed by forces acting on the channel protein
What is inactivation of a voltage gated ion channel?
special closed state which channel enters after being opened; cannot be reopened during this state
What is the composition of the Na voltage gated channel? K?
4 domains, each with 6 trans-membrane segments, pore is formed by the P-loop between S5 and S6, a voltage sensor of 4 positively charged Arg in S4 (moves with depolarization), 3-4 linker swings to inactivate ; K has a ball and chain inactivator
How is an action potential generated?
at rest almost all Na channels are closed, depolarization causes opening of some, Na ion influx causes further depolarization; positive feedback is a regenerative process that ultimately leads to all Na opening
What happens to an AP if inactivation is slowed?
broadened AP, slow sodium channel inactivation contributes to epilepsy and certain long QT syndrome
How are sodium channels blockers used pharmacologically?
local anesthetic (lidocaine), anti-arrhythmic (flecainide, lidocaine)
What is the all or none law?
becuz regenerative opening of Na channels results in the opening of virtually all Na channels, all AP in a given cell attain about the same membrane potential at their peaks no matter how strong the depolarizing stimulus
What is the absolute refractory period?
new AP cannot be generated for a brief period after an AP (membrane still repolarizing), no matter how strong the stimulus because of the large number of Na channels remaining in inactivated state
What is the relative refractory period?
threshold is elevated since some Na channels remain inactivated so fewer are available to be opened
What is the role of K channels in AP?
some K remain open at negative voltages; inward rectifier and two pore subtypes (leak channels- help establish resting potential), others are opened by depolarization- these shape AP waveforms and contribute to refractory period
What is the contribution of depolarization-activated K channels to an AP?
K channels open a bit more slowly than Na channels with the maximum number of channel opening occurring about the maximum number opening at 0.5ms after the peak of Na; opening K channels increased Pk hyperpolarization and closing of K; since tis during repolarization it speeds it; can generate after hyperpolarization which contributes to RRP
How does an AP propagate?
positive charge enters axon during an AP, build up of positive charge in axon, like charges repel, move away from point of depolarization attracted towards the negative interior further down the axon, outside the build up of negative at site of initiation attracts positive from further down, neutralization of interior negative charges and removal of outside positive charges
What determines nerve conduction velocity?
distance of electronic charge spread; further it spreads the faster the AP propagates
What effects does internal resistance have on conduction velocity?
Pin is resistance to charge through the interior of the cell; lower Pin allows charge to spread further down the inside of the axon, large axonal diameter provides more possible paths for charge to take-> lower Rin, length constant gamma is proportional to the square root of the diameter; velocity is also proportional to the square root of axon diameter
What effect does myelin have on membrane capacitance?
myelin increases conduction velocity principally by lowering membrane capacitance; reducing capacitance allows charge to spread further down the axon, increasing AP velocity
What is salutatory conduction?
AP skip from one node of ranvier to the next (often jumping two to three nodes down; conduction velocity of a small myelinated axon is the same as and axon 30x larger in diameter
Which axons are unmyelinated in humans?
small nociceptive C fibers; small in diameter; also short interneurons
What are synaptic vesicels?
spherical, contain NT stored in synaptic terminal
What is the appearance of presynaptic vesicles on EM?
docked and waiting to be released; surrounded by a dense matrix; thick membrane undercoat on postsynaptic site; vesicles typically only on one side of the synapse
What is an Omega vesicle?
when the synaptic vesicle first fuses with the membrane and releases its NT into the synapse
What is a mPSP? What produces it? What is it called at a NMJ?
miniature post synaptic potential or miniature post synaptic current (mPSC); each vesicle produces a small one; mEPP (end plate potential)
what is synaptic transmission delay? How long is it typically?
time required for vesicle fusion and diffusion of NT across synaptic cleft; ~1ms
What stimulates transmitter release?
depolarization which leads to Ca entry via opening Ca voltage gated channels in presynaptic terminal; typically due to AP but can also be due to local synaptic potential or sensory receptor potential
What is the general structure of Ca voltage gated ion channel?
4 domains, each with 6 trans-membrane segments, pore is formed by the P-loop between S5 and S6, a voltage sensor of 4 positively charged Arg in S4 (moves with depolarization), many different forms mostly with A1 subunits and accessory units
What are the most common Ca voltage gated channels?
P/Q (CaV2.1) amd N (CaV2.2)
What is Lambert-Eaton myasthenic syndrome?
associated with small cell lung carcinoma, due to autoimmune targeting of P/Q channels in motor nerve terminals
What is ziconotide used for? How does it work?
treat chronic pain; selective blocker of N-type channels; derived from toxin of fish hunting marine snail
What are the general function of the >80 proteins on a synaptic vesicle?
NT lading, docking, exocytosis and endocytosis
What are the steps in the vesicle cycle?
1) loading 2) storage 3) mobilization 4) docking 5) priming 6) calcium sensing 7) fusion 8) endocytosis
9) translocation 10) sorting
How are cationic NT concentrated into the vesicles?
via active transport; proton pump generates electrochemical gradient for NT uptake (1 pup per vesicle) then cationic transmitters (5HT) are exchanged for protons
How are anionic NT concentrated into the vesicles?
ex glutamate; use vesicular membrane potential established by proton pump
What are the V-snare proteins?
vesicle associated SNARE; synaptobrevin aka VAMP(vesicle associated membrane protein),
What are the T-snare proteins?
target-associated SNARES; syntaxin and SNAP25
What does Munc18-1 do?
helps assemble the SNARE complex
What does Synaptotagmin?
Ca sensor and fusion clamp
What do complexins do?
helps synaptotagmin clamp the SNARE complex to prevent spontaneous fusion
How do botulinum and tetanus toxins work at the NMJ?
cleave snare proteins
changes in exocytotic protiens are associate with what conditions?
neurologic and psychiatric disease; either casual role or contribute to symptoms in other diseases
What are the key exocytosis proteins?
Snare (V, T and Munc18-1), Synaptotagmin, and complexins
What do SNARE proteins do?
coil or zipper together to bring vesicle membrane close to plasma membrane; SNARE pin assembled and held in place by Munc18-1
What prevents SNARE proteins from causing spontaneous fusion ?
clamping by complexin and synaptotagmin
How does Ca binding cause release of vesicles?
binding to synaptotagmin releases the fusion clamp and thereby promotes fusion
Endocytosis of synaptic vesicles involves what? What are different mechanisms?
formation of clathirin coated pits; kiss and run or bulk retrieval of large endosomes
What is stiff person syndrome?
involves progressive muscle rigidity, painful spasms and gait impairment due to continuous motor activity; subset associated with breast cancer associated serum antibodies to amphiphysin- cytoplasmic vesicle protein, along with dynamin, helps with membrane fission during endocytosis
Where is glutamate used as a NT? excitatory or inhibitory?
principle excitatory NT at CNS synapses
Where is ACh used as a NT? excitatory or inhibitory?
excitatory NT at NMJ
Where is GABA used as a NT? excitatory or inhibitory?
principle inhibitory NT in brain
Where is Glycine used as a NT? excitatory or inhibitory?
principle inhibitory NT in spinal cord
What are the two main types of NT receptors?
fast ionotropic (ligand-gated ion channels) and slow metabotropic (GPCR- AngII in brain utilizes this to inhibit K channels)
How do NT and receptor types match up?
a NT can activate subtypes of both ionotropic and metabotropic
What are the receptor subtypes for glutamate?
ionotropic: AMPA (GluR1-4), Kainate (GluR5-7), NMDA (NR2A-D); metabotropic: mGluR1-8
What is myasthenia gravis?
involves autoimmune rxn that destroys ACh receptors at NMJ causing muscle weakness or paralysis
What drugs act by blocking NT receptors?
curare (nicotinic AChR), atropine (muscarinic AChR)
What determines whether a NT will have an inhibitory or excitatory effect?
by the type of ion channels that are opened or closed
In chemical synapses what channels does Na use to get into the post synaptic cell?
through the opening of Na permeable cation channels leading to depolarization; transmitter-gated non-selective cation channels, moves membrane potential closer to threshold (1/2 way between Ena and EK) -> EPSP
What NT open non-selective cation channels?
glutamate or ACh
How is inhibition of post synaptic neuron achieved?
influx of K by opening K permeable channels; no transmitter but opened indirectly via metabotropic receptor activation
Activation of ionotropic GABA and Glycine receptors triggers what?
opening of Cl channels; typically causes membrane hyperpolarization since Cl equilibrium is usually slightly negative (more outside cell than inside so moves down [Cl] gradient), inhibitory (IPSP)
What is the makeup of electrical synapses? example?
gap junctions; two adjacent gap junction hemichannels or connexons in neighboring cells to form the gap junction; found in the retina
What is temporal summation?
at most CNS synapses; coincident arrival of multiple EPSPs arriving at nearly the same time are summed and inhibitory can decrease; if not summed an individual EPSP decays;
What is spatial summation?
PSPs travel down the dendrites and are summed in the soma; distance it spreads down the dendrite is determined by length constant; wider diameter the longer the length constant
When can Cl channels have no effect or depolarizing effect on PS neuron?
particularly in fetal neurons; if Cl is high inside the cells, opening channels causes an efflux through GABA and glycine receptors; important in neuro development; if Cl is in equilibrium then there will be no change
How can inhibition occur with out hyperpolaization
if Cl is in equilibrium then there will be no change; can cause shunting of membrane resistance and still inhibit without hyperpolarizing
PSPs arise from what?
PSCs; ion currents resulting from NT-gated opening of ion channels; EPSC x Rm (membrane resistance) = EPSP
How is ACh synthesized?
one reaction acetyl-CoA and choline to ACh and CoA via choline acetyltransferase; choline from diet
What are the ACh neurons?
motor of spinal cord- at all vertebral levels released at NMJ, Autonomic- NT of presganglionic, PS- postganglionic NT, CNS (ex nucleus basalis)
Decreased NT production in the nucleus basalis is seen in what conditions?
some forms of dementia; leads to decreased learning and mental capacity
What is the clinical presentation and cause of organophosphate poisoning? (insecticides)
inhibits AChE, elevated levels of ACh overstimulates nicotinic and muscarinic receptors; SLUDGEM- salivation, lacrimation, urination, defecation, GI motility, emesis, miosis
What are the 4 major tracts that utilize dopamine?
Mesolimbic-Mesocortical: emotional and cognitive circuitry (schizophrenia), Nigrostriatal tracts: control of movement (Parkinsons), Tubero-infundibular tracts: regulation of hormone secretion (DA inhib of prolactin), Medullary-periventricular: regulation of feeding (obesity and diabetes)
How is NE synthesized?
dopamine (precursor tyrosine) via dopamine-B-hydroxylase (bound to inner surface of vesicle)
What neurons use NE?
cell bodies located in locus coeruleus in CNS, in PNS used in postganglionic sympathetic
How is epinephrine synthesized?
by mehtylating NE, SAM is methyl donor (s-adenosyl methionine), SAM localized in the cytoplasm, must exit vesicle and reenter; used only by a few neurons
How is serotonin synthesized?
5-HT, from tryptophan hydroxylated via tryptophan hydroxylase
What neurons utilize 5-HT?
localized to neurons in midline of brainstem, projections throughout CNS; involved in regulating attention, complex cognitive functioning and depression
How is histamine synthesized?
from histidine by histidine decarboxylase
What neurons utilize histamine?
in posterior hypothalamus, promotes release of E and NE (neuromodulator); involved in regulating arousal, body temp, and vascular dynamics
What neurons use glutamate as a NT? How is it degraded or removed?
primary excitatory of CNS; reuptake into neuron and glia; astrocytes convert to glutamine and diffuse it back to neurons where it is hydrolyzed to glutamate by glutaminase
How is GABA synthesized? What neurons use it?
from glutamate catalyzed by glutamic acid decarboxylase, primary inhibitory NT of CNS
What neurons utilize glycine as a NT?
inhibitory NT, particularly in interneurons of spinal cord; activation by glyine allows Cl to enter via ionotropic -> IPSP, co-agonist with glutamate for NMDA receptors which results in excitation
What are properties of neuropeptides and how are they synthesized?
synthesized by mRNA in cell body, transported to presynaptic terminal, derived from pro-hormones, stored in large vesicles, release by Ca, higher potency and longer lasting than small NT, act thru GPCR as neuromodulator or NT
What are examples of neuropeptides and their roles?
CCK- role in satiety, somatostatin- inhibits GH, NPY- plays a role in seizure and appetite control, Substance P- pain perception, regulation of mood and anxiety, AngII- contributes to CV and body homeostasis
What NT bind to ionotropic receptors?
Ach, glutamine, GABA, glycine, serotonin (some bind both)
What are the characteristics of nicotinic receptors(ionotropic)?
ACh, also activated by nicotine, excitatory, K, Na, and Ca permeable, skeletal motor end plate, autonomic ganglia, CNS, many isoforms; some allow Ca and others gen cation
What are the characteristics of glutamate receptors(ionotropic)?
excitatory, Na, K, and CA permeable, numerous subtypes (NMDA, AMPA, kainite), wide CNS distribution, structurally distinct from the nicotinic receptor
What are the characteristics of serotonergic receptors(ionotropic)?
excitatory, Na, K, and Ca pemrable, localized in GI and CNS, structurally similar to nicotinic; cognition/depression
What are the characteristics of GABAergic receptors(ionotropic)?
inhibitory, cl permeable, 6 different alpha subunits, 4 beta, 3 gamma; many isoforms, wide CNS distribution, structurally similar to nicotinic
What are the characteristics of glycine receptors (ionotropic)?
inhibitory, permeable to Cl, localized in spinal cord and brain stem, structurally similar to GABA and nicotinic
What are the general features of metabotropic receptors?
GPCR, slower acting, excitatory or inhibitory, increase or decrease cAMP accumulation, changes intracellular Ca occur
What are the different metabotropic receptor types?
cholinergic, dopaminergic, glutamate, adrenergic, GABAergic and serotonergic
What are the features of Cholinergic metabotropic receptors?
ACh muscarinic, 5 subtypes (m1-m5), excitatory or inhibitory
What are the features of dopaminergic metabotropic receptors?
5 subtypes (d1-d5), excitatory; contribute to motivation, pleasure, cognition, learning, and fine motor control
What are the features of glutamate metabotropic receptors?
8 subtypes (mGluR1-mGluR8), excitatory or inhibitory
What are the features of adrenergic metabotropic receptors?
NE and Epi, excitatory or inhibitory, alpha 1 and 2, beta 1-3
What are the features of GABAergic metabotropic receptors?
receptor for GABAb, linked to K channels, inhibitory
What are the features of seritonergic metabotropic receptors?
5-HT1 is inhibitory; 5-HT2 is excitatory
What are the methods of cellular reuptake of NT?
reuptake into axon terminal that released it (NE, Epi, DA, Serotonin) can be reused; or glial cell transporters, astrocytes remove from synaptic cleft (glutamate via EAAT- excitatory amino acid transporters)
What are the methods of NT extracellular destruction?
diffusion-NT drifts, can no longer act; or enzymatic degradation so it is no longer recognized (ACh via AChE or neuropeptides to peptidases)
Glutamate induced neurotoxicity involves what conditions?
acute insults to the brain (ischemia, traumatic brain injury) and neurodegeneration (amyotrophic lateral sclerosis, parkinsons)
What are the mechanisms on a cellular level that lead to neurotoxicity?
increased glutamate release, reduced glutamate uptake by glial cells, hypersensitivity to NMDA receptors or increase metabotropic glutamate signaling, impaired Ca homeostasis, and mitochondrial dysfunction
What are the features of the NMDA receptor?
3 diff subunits(NR1, NR2[A-D], NR3{A-B}); NMDAR activation results in cation influx (Ca; Na and K can pass resulting in depolarization and activation of voltage Ca), glycine required for glutamate activation of NMDAR; Mg blocks and Zn binding can inactivate
What are the features of the AMPA receptor?
made of combo of 4 diff subunits (GluR1-4), requires only glutamate for activation, AMPAR-mediated cation influx depends on composition: GLuR1,3,4 allow Ca influx and GluR 2 inhibits Ca influx; regulate Ca influx thru NDMAR by removing Mg
What are the features of the Kainate receptor?
made of combo of 3 diff subunits (GluK 5-7 and Ka 1-2); similar to NMDAR and AMPAR allow for ion influx; more closely to AMPAR because play a role in removing Mg block of NMDAR
What are the 3 categories that mGluR 1-8 are categorized into?
group I- potentiate NMDAR induced Ca influx (1 and 5), PLC, IP3; Group II- decrease adenylyl cyclase, inhibit voltage dependent Ca channel (2-3); Group III- decreased adenylyl cyclase, inhibit voltage dependent Ca channel (4,6,7,8)
What is the link between calcium and neuronal toxicity?
excessive [Ca] intracellular activates signaling pathway, associated with mitochondria dependent apoptosis, Ca required for nNOS activation leading to NO production, can also increase ROS resulting in irreversible oxidative damage
How does Ca increase ROS?
Ca overload damages ETC causing electrons to leak off and onto O2-> ROS, this is associated with cytochrome C release from mitochondria and activation of caspases-> death signal
How are EEATs regulated?
by kinases including PKC and PKA and PI3K
What is altered expression/function of EEATs associated with?
cerebral ischemia, traumatic brain injury, Parkinsons, Alzheimers and amyotrophic lateral sclerosis; increased ROS levels can inactivate EAAT via oxidative damage
What are the clinical features of ALS?
diagnosed combo UMN- slow speech, brisk gag and jaw jerk, brisk reflexes and spasticity and LMN- muscle atrophy, fasciculations and weakness; diagnosis of exclusion
What is ALS?
fatal, specifically targets motor neurons of spinal cord, brain stem and cortex, onset with weakness in arms and legs and quickly progresses to total paralysis, die w/in 2-5 yrs of respiratory failure,
What is the cause of ALS?
glutamate induced excitotoxicity, impaired uptake from synaptic cleft due to dysfunction/loss of EAAT
How does cerebral ischemia cause excitotoxicity?
decreased O2 and glucose, decreased ATP, ATP-dependent pump fails, neurons depolarize, glutamate release, NMDAR activation, increased influx of calcium, neuronal toxicity
How does the drug Riluzole work in ALS?
slows progression, inhibits gluatamte release, inactivations of Na voltage-gated, and inhibition of intracellular signals following glutamate receptor activation
How is huntigtons associated with excitotoxicity?
mutant htt protein increases NMDAR activity
How is Alzheimer’s associated with excitotoxicity?
extracellular deposition of B-amyloid peptide may compromise glutamate signaling, excessive activation of NMDA, memantine-NMDAR antagonist used to tret sysmtpoms not a cure
How is Parkinsons associated with excitotoxicity?
decreased expression of parkin, gene product of PARK2 associated with hereditary parkinsons or mutant parkin increases proliferation of glutaminergic synapses
