Unit 1 - Basic properties of NS Flashcards
Ways for Na+ and K+ to cross neuron membrane
- proton pumps - low turnover rate
2. ion channels - high turnover rate (more effective!)
Major properties of Ion Channels
- Gated! (voltage, ligand, or mechanical/stress-gated)
- selective permeability
- voltage-gated: K+, Na+, Ca+
- ligand-gated: cation (K+, Na+…Ca2+) OR anion (Cl-) selective - HIGH flux rates! (efficient in transporting ions)
type 1 episodic ataxia
loss of muscle coordination due to a genetic disorder of ion channel(s)
–> mutation in voltage-gated K+ channels
Type 2 episodic ataxia
loss of muscle control due to genetic disorder of ion channels
–> point mutations in voltage-gated Ca2+ channels
= exercise induced
voltage-gated Na+ channel mutations
change function of ion channels –> affect pain sensation
- most mutations in Nav1.7 –> hyperexcitability (excessive pain sensation)
- nonsense mutations in Nav1.7 –> NO pain sensation
structure of voltage-gated Na+ channels
4 repeats, each with 6 membrane-spanning domains.
BUT only 1 protein forms the whole channel (encoded by 1 gene)
- H5 (aka P region) = pore-forming portion
- S4 domain = voltage gating portion
(conf. change to shift + charge –> open channel)
Criteria for Neurotransmitters (NTs)
- synthesized in neuron
- Stored in presynaptic nerve terminal
- Mechanism for release (tied to stimulation, usually Ca2+ dependent)
- mechanism for degradation (in synapse)
Vesicular transporters
on presynaptic vesicles, swap transmitter for H+ 4 types (for ACh, Gaba, glutamate, amines)
Mechanism of Small molecule NT synthesis
(Ach, NE, Gaba, etc.)
- synthesize enzymes in soma;
- transport enzymes to presynaptic terminal
- synthesis and packaging of NTs IN presynaptic terminal
- -> release of NT (synthesis and release of these is FAST!)
Lambert-Eaton Myasthenic Syndrome
Autoimmune attack on pre-synaptic calcium channels, decreases the # quanta released at NMJ.
- -> muscle weakness, reduced tendon reflexes, ANS dysfunction
- associated w/ small cell lung carcinoma
Major parts of a neuron
- dendrite (receives signals, no myelin –> signals degrade towards soma)
- soma (cell body, w/ all cell machinery, ER, nucleus, etc.) aka: perikaryon
- Axon (sends signals to next target - ie: neuron or muscle)
Axon Hillock
junction btwn soma and axon, where the AP is initiated in axon.
- -> “center of electrical excitement”
- w/ high amt Na+ channels*
2 types of glial cells
= supporting cells for neurons, 10x # neurons!
- oligodendrocyte - in CNS
- Schwann cell - in PNS,
Golgi stain used for?
Golgi stain –> dendrites appear black.
- allows study of structure of dendrites in tissue
ie: pyramidal in cortex
Motor axons synapse on…?
Motor end plate!
motor axons don’t actually synapse directly on muscle
convergence
Any one neuron can receive many different axonal projections
divergence
Any one neuron can send axonal projections to many targets (ie: other neurons)
spines
= small projections off dendrites (look like tree buds),
w/ NTs and ion channels
–> expand signal receiving area of the dendrite
speed of signal transduction depends on…
- diameter of the axon – INcrease speed
(0.2 - 20 m^-6 –> 120-235 m/s) - resistance
- myelination –> INcrease speed
(external resistance)
molecular transport along axon
- uses microtubules as highways for molecular transport to either end of axon.
- anterograde: from soma to pre-synaptic terminal
(NTs - whole or parts, vesicles, proteins, lipids) - retrograde: from pre-synaptic terminal to soma (GF, rabies virus)
speed of molecular transport along axons
- organelles/molecs: ~400mm/day
- cell structures: SLOW. 0.2 mm/month
- -> neurons grow VERY slowly! (hard to regrow when damaged)
Parts of CNS
- Brain
- Spinal cord
- -> collection of cell bodies = “nucleus”
parts of PNS
- Cranial nerves (CNI-XII)
- spinal nerves (motor and sensory)
- cervical (8), thoracic (12), lumbar (5), sacral (6), coccygeal.
- -> collection of cell bodies = “ganglion”
- cervical (8), thoracic (12), lumbar (5), sacral (6), coccygeal.
White matter
neural tissue rich in myelinated axons
gray matter
neural tissue consisting mostly of cell bodies (soma)
decussate
when a nerve/neural tract crosses the midline
ie: opti chiasm
Na+/K+ ATPase
Active ion transporter, powered by ATP hydrolysis;
establishes K+/Na+ gradient.
* LOW rate of turnover –> 10^3 cycles/sec.
–> not fast enough to cause depolarization or hyperpolarization
Ion channels for Neural signaling
* used to QUICKLY change membrane potential for AP, HIGH flux (turnover rate): ~10^7 - voltage-gated (Ca++, Na+, K+) - ligand-gated (K+, Na+, Cl-) - mechanical
rectification
When make the inside of a neuron positive, the cation channel will open; if make negative, the channel will stay closed.
TEA (tetraethylammonium)
toxin that blocks delayed rectifier K+ channels
- sometimes used in voltage clamping to isolate specific channels
K+ leakage channel
(aka: TASK-1 channel) = open at resting potential, helps w/... - generate resting potential - falling phase of AP.
Voltage-gated Na+ channel
4 repeats of 1 protein, similar activation curve to volt-gated K+ channel, BUT…
- Faster activation
- self-INactivating (ball and chain model)
- must hyperpolarize before second depolarization
- Blocked by TTX (tetrodotoxin) and STX (Saxotoxin, in red tide)
Voltage-gated Ca+ channel
= 1 continuous protein (similar to Na+ channel); But: longer C terminal, w/ more bindings.
L-type - high volt. activated. in skeletal mm and neurons;
- sensitive to dihydropurines
N-type - High volt. activated, in pre-synaptic terminals
T-type - LOW voltage activated **all types have varied inact. time
Functions of Ca+ in neurons
- Release of vesicles from pre-synaptic terminals
- muscle contraction
Internal [Ca++]…
- modulates other ion channels - Enzyme activation
- process outgrowth and synaptic plasticity - gene expression
Patch Clamp
= test for a SINGLE ion channel, measures channel conductance.
- conductance is constant (= 1/resistance)
- transition btwn open and closed is instantaneous
Resting Potential
the potential of a neuron at rest (not firing); primarily reflects Ek.
- net charge across membrane MUST be neutral
- maintained by Na+/K+ ATPase
- deviates from Ek at very LOW [K+]!
- different than equilibrium potentials (when 1+ ion in permeable)
Electrochemical Equilibrium Potential
the voltage at which a) and b) balance each other out.
a) flux due to chemical gradient
b) flux due to voltage (charge) gradient
* measured for single ions (Ek, Ena), also for net membrane (Em)
Nernst potential
Calculates the Electrochemical Equilibrium value for a given ion.
Eion = V= (58/z)*log([ion]out/[ion]in)
* z= charge of ion (ie: Ca = +2, Cl = -1)
GHK Equation (Goldman-Hodgkin-Katz)
Calculates membrane electrochemical equilibrium (Em),
takes into account all permeable ions.
Em = (58/z)log((Pk[K]o + Pna[Na]o + Pcl[Cl]i)/(Pk[K]i + Pna[Na]i + Pcl[Cl]o))
* P = relative ion permeability –> Pk usually»_space; Pna
Characteristics of Action Potential
- All-or-Nothing / must meet threshold to get AP
- Rapid, no decrement
- rising and falling phases
- positive feedback (some depolarization makes more reaching threshold easier)
Generation of an Action Potential
- (resting) K+ leakage channels maintain Em
- (rising) open Na+ channels –> depolarize {Na+ INTO cell}
- (falling) Na+ channels INactivate, close;
K+ rectifier channels open, {K+ into cell, Na+ out of cell}
K+ leakage channels open –> re-and hyper-polarize
Maximum length of a dendrite
1/2 mm
range in size from 100s of microns to 0.5 mm
Voltage-gated K+ channel structure
made of glycoprotein, 4 subunits each w/ 6 transmembrane domains. Internal phosphorylation sites.
- P region (aka: H5) = pore
- S4 = voltage-sensor
- -> moving domains “opens” pore
characteristics of dendrites
channels = ligand-gated, potential = mvmt of ions down dendrite (passive conductance) --> spatial and temporal summation - decremental potential * not myelinated
Characteristics of axons
channels = voltage-gated (esp. dense at axon hillock)
conductance = active, fast, non-decaying (= electrical signal)
* usually myelinated
– oligodendocytes in CNS
– schwann cells in PNS
Multiple Sclerosis
autoimmune disease where CNS myelin is degraded –> paralysis.
* WORSE w/ heat/high temps bc conductance of axons decreases.
(reduce symptoms when cooler)
time constant
the time that it takes for a potential (AP) to reach 63% of its final amplitude
Tau = RC (R = resistance, C = capacitance … both of membrane)
* should be same for depolarization as hyperpolarization
Length constant
the distance at which the voltage of a potential decays to 37% of the maximal amplitude.
lambda = 0.5square root(d(Rm/Ri))
Rm = membrane resistance, d = diameter (ie: 0.1 microm)
Ri = cytoplasmic (internal) resistance
** important for spatial summation in dendrites and placement of Nodes of Ranvier in axons**
relationships btwn length constant, speed of propagation, and diameter
increase d –> increase length constant;
increase length constant –> increase velocity (of propagation)
effect of myelin on signal propagation
insulates the membrane,
- -> INcrease membrane R
- -> DEcrease membrace C (capacitance)
Characteristics of electrical synapses
= Gap Junctions (connexon w/ 6 connexins, rotated = active.)
- electrically AND chemically couples adjacent cells;
- synchronizes neural activity, esp. in astrocytes in CNS
- Bi-directional signaling
- excitatory only, No desensitization
Characteristics of chemical synapses
(most common type of synapse)
- response depends on Receptor type (EPSP or IPSP)
- can cause Long-term potentiation (“LTP”)
targets: motor end plates, other neurons’ dendrites
general mechanism of chemical synapses
- AP depolarizes pre-synaptic terminal
- release vesicle into synaptic cleft
- NT binds to R on post-synaptic neuron
- response and NT degradation/re-uptake
MEPP
"Mini EndPlate Potential" spontaneous release of a SINGLE vesicle (~3,000 NTs) = 1 "quanta" --> ~0.3-1 mV CNS: releases few quanta/excitation PNS: releases ~150 quanta/excitation
mechanism of synaptic release
- Ca2+ influx at active zones of pre-syn. terminal (bc depolarized)
- a) Syntaxin binds to Ca2+ channel (holds open) -> Fusion pore
b) SNAREs bind vesicle to membrane
c) Synaptotagmin (Ca-dep.) –> fusion of vesicle w/ membrane 3. Ca-dep. protein kinases trigger vesicle release
reasons for synapse plasticity
- AP duration varies
- Ca2+ regulation varies
- synaptic potentials summate (temporal and spatial)
- -> can cause: Long-term potentiation/depression (new memory!)
Unconventional NTs
- NO and CO: gases, retrograde NTs, not stored.
- NO gas activates the pre-synaptic channel
- Endocannabinoids: alter NT release by binding to pre-synaptic Rs (allosterically)
Botulinum and Tetanus toxins
= internalized at pre-synaptic terminal,
selectively attack synaptobrevin and other vesicle-release factors.
–> permanently INactivate the synapse (!)
Clinical correlation: diseases w/ NT deficiencies
- Alzheimer’s: lack ACh
- Parkinson’s: lack Dopamine
- Depression: lack monoamines
characteristics of small molec NTs
ACH, AAs (glutamate) and catecholamines;
- binds to ionotropic Rs;
- synthesized at terminal, stored in small vesicles;
- fast or slow rate of action
- inactivation by reuptake
characteristics of Peptide NTs
ie: somatostatin, angiotensin, NPy, opioids; (3-30 AAs)
bind to metabotropic Rs; * f(x): CNS neuromodulation*
- synthesized in golgi (in soma), stored in Dense-core vesicles
- slow rate of action
- inactivation: enzymatic degradation (no reuptake)
Characteristics of Ionotropic NT receptors
ligand-gated ion channel (direct action),
- fast excitatory OR inhibitory response
- binds: ACh (nicotinic), GABA-A, and AMPA
Characteristics of metabotropic NT receptors
GPCRs that activate cascade and alter gene expression;
(indirect action w/ NT binding)
- slow, long-lasting response (can modulate neuron)
- bind: dopamine (D1 and D2), GABA-B, ACh (muscarinic), and NE-alpha and beta
ACh synthesis and degradation
- AcetylCoA + choline –> ACh via “CAT” (choline acetyl transferase)
- ACh –> acetate + choline via “AChE” (acetylcholinesterase)
nicotinic ACh Receptor (nACh R)
heteromeric w/ 5 subunits, binds 2 ACh to open.
- ionotropic
- excitatory – nicotine = agonist
- permeable to: Na+, K+, Ca++, Mg++
- in NMJ, autonomic ganglia, and CNS (esp. basal forebrain)
Muscarinic ACh Receptor (mACh R)
5 types (M1-5)
- metabotropic
- in CNS and PNS
- M2 opens K+ channels
- muscarine = agonist
Anti-cholinesterases
prevent ACh degradation in synapse by blocking AChE;
- -> increase amt ACh in cleft
- edrophonium: reversible in NMJ
- parathion: IRreversible
- used to treat Myasthenia Gravis but not Lambert-Eaton
GABA synthesis and degradation
- Glutamine –> glutamate via glutaminase
- glutamate –> GABA via GAD (Glutamine decarboxylase)
* removed by reuptake* - GABA –> Glutamate via GABA-transaminase
- Glutamate –> Glutamine via Glutamine synthase
GABA-A Receptor
- ionotropic R,
- fast response
- permeable to Cl-
- IPSPs in CNS
anti-epileptic drugs
work on GABA-A receptors,
–> cause allosteric potentiation
Ex: benzodiazepines and barbiturates
GABA-B receptor
metabotropic receptor w/ 7 transmembrane domains
- -> IPSP
- slow response
- works on pre- and post-synaptic sites
Glycine receptor
ionotropic receptor, most present in ventral spinal cord
- IPSP
- increases Cl- permeability in post-synaptic membrane
- strychnine = agonist
Glutamate Receptors
** can be neurotoxic (excitotoxicity), esp. in CNS,
removed from synapse by re-uptake.
AMPA R: fast, EPSP, ionotropic; increase gNa+ and gK+
Kainate R: fast EPSP; increase gNa+ and gK+
NMDA R: fast EPSP; increase gNa+, gK+, and gCa2+ ** Mg block!
mGlu R: slow, EPSP or IPSP, metabotropic; ** LTP!
coincidence receptor
NMDA R (binds glutamate);
has voltage-dependent Mg2+ block
–> only opens after some depolarization has accumulated
Catecholamine synthesis
= Dopamine and NE (norepinephrine).
- Tyrosine –> L-DOPA via TH (tyrosine hydroxylase) *RDS!
- L-DOPA –> Dopamine via AAAD (DOPA decarboxylase)
- Dopamine –> NE via Dopamine Beta Decarboxylase
Catecholamine NT Inactivation
3 ways, enzymes OR reuptake.
- MAO (monoamine oxidase)
- COMT (catechol methyl transferase)
- Reuptake (DAT or NET, = Na+ coupled Rs)
* *blocked by cocaine and amphetamine
most NE and Dopamine R neurons in…
NE: pons and medulla to striatum
Dopamine: midbrain (esp. substancia nigra and ventrotegmental area) to striatum
both in CNS and PNS
Parkinson’s Disease
dopamine deficiency from neural degeneration in substancia nigra
(controls mvmt)
* treat w/ L-DOPA (pro-drug so can pass blood-brain barrier)
clinical depression
complex, but often decreased catecholamine or serotonin f(x);
ie: receptor deficiency
* treat w/ MAOs or TCA to increase amt of NT at synapse
types of Norepinephrine receptors
all = metabotropic, IPSP or EPSPs;
- alpha-adrenergic 1 and 2
- beta-adrenergic 1 and 2
Dopamine Receptors
= metabotropic
- D1: post-synaptic
- D2: pre/post-synaptic
Serotonin synthesis and inactivation
- tryptophan –> 5-HTP via tryptophan hydroxylase
- 5-HTP –> 5-HT (serotonin) via AADC
Inactivation:
- MAO
- reuptake by SERT **blocked by prozac
serotonin receptors
location: mostly in gut, but also raphe nucleus (brainstem)
types:
metabotropic: 5-HT 1a, 1b, 1d,1e and 5-HT 2a, 2b, 2c
* 1B and 1D = pre-synaptic auto-receptors
ionotropic: 5-HT 3
Endocannabinoids as NTs
retrograde, unconventional NTs;
- made from lipids by Ca2+/mGluR activation
- diffuse freely through membrane
- bind to CB1 and CB2 receptors in brain
- interact w/ pre-synaptic volt-dep. Ca2+ channels
NO gas as NT
unconventional, retrograde NT;
L-arginine –> NO via NOS, triggered by glutamate (via NMDA Rs and increased Ca2+)
- synthesized in post-synaptic terminal, not stored
- passive inactivation (very short half life)
–> 2nd messengers in pre-syn. site **in hippocampus and LTA **
thalamus
part of diencephalon, w/ “internal capsule”;
transmits info from subcortical structures to cortex AND relays cross-cortical info.
(sensory and motor, but NOT olfaction)
- glutamatergic (EPSP, to cortex) and GABAergic (IPSP, local) Rs
Anterior nucleus (A)
thalamic nucleus, relay fibers;
input: mammillothalamic tract and hippocampus
output: cingulate gyrus
Ventral Anterior Nucleus (VA)
thalamic nucleus, relay fibers;
input: basal ganglia
output: motor areas (ie: primary motor area)
Ventral Lateral Nucleus
thalamic nucleus, relay fibers;
input: cerebellum
output: Motor areas (ie: primary motor area)
Ventral Posterolateral (VPL)
thalamic nucleus, relay fibers;
input: Body portion of medial lemniscus and spinothalamic tract
output: somatosensory cortex
Ventral posterolateral nucleus (VPM)
thalamic nucleus, relay fibers;
input: Face part of medial lemniscus and trigeminothalamic tract
output: somatosensory cortex
Medial Geniculate Nucleus (MGN)
thalamic nucleus, relay fibers;
input: branchium of inferior colliculus
output: auditory cortex
Lateral Geniculate Nucleus (LGN)
thalamic nucleus, relay fibers;
input: optic tract
output: visual cortex
dorsomedial nucleus (DM)
thalamic nucleus, association fiber(s);
input: prefrontal cortex, olfactory and limbic structures
output: prefrontal cortex
Pulvinar
thalamic nucleus, association fiber(s);
input: parietal, occipital, and temporal lobes
output: prefrontal cortex
pyramidal neurons
type of neuron in cortex, aka: Betz cells in primary motor area;
large soma, EPSP, long axons that leave the cortex.
- intracortical: layers II and III
- subcortical: layer V
- corticothalamic: layer VI and some of V
spiny stellate neurons
small, star-shaped neuron in cortex,
only local connections, no apical dendrites;
= layer IV of primary sensory areas
* main target of thalamocortical axons*
Local circuit neurons
local, inhibitory neurons in cortex.
many types (no specifics to memorize).
** imbalance of cortical activity (poor modulation) –> autism
Layer I of neocortex
few soma, near pial surface
layer II of neocortex
small pyramidal neurons,
cortico-cortical signaling
layer III of neocortex
larger pyramidal neurons,
cortico-cortico signaling
layer IV of neocortex
spiny stellate in primary sensory areas (only),
receives thalamocortical axons,
Areas: 17-visual, 3- somatosensory, 41-auditory;
* esp. thick in granular cortex*
layer V of neocortex
large pyramidal neurons,
communication to brainstem and spinal cord, OR thalamic association areas (DM and pulvinar)
Area 4! (w/ Betz cells).
layer VI of neocortex
communicates directly to thalamus
