Final-HLO

the heart does calcium-induced-calcium-release , skeletal muscle uses direct contact of ryanodine receptors instead
How to Increase Conduction Velocity :
1. add myelin
  - increases resistance ( less leak )
  - decreases capacitance ( more distance between inside and outside of cell )
2. increase length between internodes
  - fewer nodes = fewer sites where the AP needs to regenerate , saving time
3. increase internal diameter ( giant squid )
  - lower cytosolic resistance ,
    - allows charges to diffuse easier / faster

Acute Inflammatory Demyelinating Polyradiculoneuropathy ( AIDP )
- autoimmune attack demyelination on PNS nerves
- Guillain-Barre type
Multiple Sclerosis ( MS ) :
- autoimmune attack on oligodendrocytes ( CNS )
  - loss of myelin
- disrupted paranodal and nodal organization
- treatment = K+ channel blocker

Myasthenia Gravis ( MG ) :
- autoimmune attack on skeletal muscle neuromuscular junction ACh receptors
- treatment = acytlecholine esterase inhibitors
  - but the balance is tricky , because too much inhibitor will cause too much available acetylcholine
    - then the receptors will naturally become desensitized on their own due to excess ACh
If you voltage clamp some muscle fiber at -90 mV vs clamping it at -20 mV ,
- the one clamped at -90 will have a much larger current measured
  - there is a larger driving force for acetylcholine

Neurotransmitter	Receptor Type	Subtype Name	Other Names / Notes	Ions Conducted	Effect
Acetylcholine (ACh)	Ionotropic	Nicotinic	Ligand-gated ion channel	Na⁺ in , K⁺ out ( some also Ca²⁺ permeable )	Excitatory
	Metabotropic	Muscarinic	GPCR ( M1–M5 subtypes )	— ( via second messengers )	Usually excitatory ( M1 , M3 , M5 ) or inhibitory ( M2 , M4 ) depending on subtype
Glutamate	Ionotropic	AMPA , Kainate	Ligand-gated ion channels	Na⁺ in, K⁺ out	Excitatory
	Ionotropic	NMDA	Requires glycine co-agonist , voltage-gated Mg²⁺ block	Na⁺, Ca²⁺ in, K⁺ out	Strong excitatory , Ca²⁺-dependent signaling
	Metabotropic	mGluR ( types 1–8 )	GPCRs	— ( via second messengers )	Modulatory ( can be excitatory or inhibitory )
GABA	Ionotropic	GABA_A	Ligand-gated Cl^– channel	Cl^– in ( hyperpolarizes )	Inhibitory
	Metabotropic	GABA_B	GPCR activating K⁺ channels, inhibiting Ca²⁺ channels	↑ K⁺ out , ↓ Ca²⁺ in ( via second messenger )	Inhibitory
Glycine	Ionotropic	Glycine receptor	Ligand-gated Cl^– channel	Cl^– in ( hyperpolarizes )	Inhibitory
	Metabotropic	— ( none )	No known metabotropic receptor	—	—

Receptor	Kinetics	Calcium Permeable ?	Voltage Dependent ?
AMPA	Fast	No	No
NMDA	Slow	Yes	Yes ( via magnesium block )

Dopamine for example can bind to both stimulatory and inhibitory GPCRs

Extracellular magnesium is used to block / inactivate NMDA channels at negative potentials

Heuser Paper :
- Hypothesis = synaptic vesicle exocytosis underlies quantal neurotransmitter release
  - one synaptic vesicle fusing with the membrane corresponds to one quantum of neurotransmitter release,
    - and these events occur independently at the presynaptic active zone
- Conclusions :
  - Each vesicle undergoing exocytosis corresponds to a quantum of neurotransmitter release
  - Vesicle fusion events are independent, not cooperative
  - Quick-freezing successfully captures exocytosis events.
  - 6At low levels of release, collapsed vesicles must be included to match quantal output
- Evidence :
  - Freeze-fracture electron microscopy captured vesicles fusing with the membrane 5–6 ms after nerve stimulation, matching the timing of neurotransmitter release.
  - 4-aminopyridine (4-AP) was used to increase quantal output, showing a dose-dependent increase in vesicle exocytosis events.
  - Quantitative correlation: The number of vesicles fusing matched the number of quanta released, across low to high 4-AP concentrations.
  - Spatial analysis showed vesicle openings occur precisely at active zones, not elsewhere, and are randomly distributed, supporting independent vesicle fusion.
  - At lower 4-AP doses, inclusion of collapsed vesicles (early fusion stages) improved correlation with physiological data.
  - No evidence for synchronized or cooperative fusion — each vesicle acts independently.
- Together, this evidence strongly supports the hypothesis that synaptic vesicles fuse with the membrane to release neurotransmitter quanta, and that this can be directly visualized and quantified using high-resolution, time-locked quick-freezing techniques.
$m$ using method of failures :
$m = l n (\frac{# t r i a l s}{# f a i l u r e s})$

Feature	Synaptobrevin ( zipper ) KO (VAMP KO)	Synaptotagmin ( sensor / brake ) KO
Evoked Amplitude	↓↓↓ ( almost abolished )	↓↓↓ ( almost abolished )
Evoked Frequency	↓↓↓	↓↓↓
Mini Amplitude	↓ ( reduced )	increased
Mini Frequency	↓↓↓ ( very rare )	↑ ( increased spontaneous fusion )
Docking	unaffected , they still dock	decreased
Fusion	they don't fuse	Ca²⁺-triggered fusion defective; spontaneous fusion increased

Protein/Channel	Location	Direction (From → To)	What is Moved
ORAI1	Plasma membrane	Extracellular space → Cytosol	Ca²⁺ (influx)
STIM1	ER membrane	—	Senses low ER Ca²⁺
TRPC	Plasma membrane	Extracellular space → Cytosol	Ca²⁺ / Na⁺ (non-selective cation)
PMCA	Plasma membrane	Cytosol → Extracellular space	Ca²⁺ (ATP-dependent)
SERCA	ER membrane	Cytosol → ER lumen	Ca²⁺ (ATP-dependent)
RyR	ER membrane	ER lumen → Cytosol	Ca²⁺ (CICR)
Ins(1,4,5)P₃R	ER membrane	ER lumen → Cytosol	Ca²⁺ (via IP₃)
MCU complex	Mitochondrial inner membrane	Cytosol → Mitochondrial matrix	Ca²⁺
VDAC	Mitochondrial outer membrane	Cytosol → Intermembrane space	Ca²⁺ and other metabolites
TRPML1	Lysosomal membrane	Lysosome → Cytosol	Ca²⁺
Cav channel	Plasma membrane	Extracellular space → Cytosol	Ca²⁺ (voltage-gated)
BKCa channel	Plasma membrane	Cytosol → Extracellular space	K⁺ (Ca²⁺-activated)
CaCC channel	Plasma membrane	Cytosol → Extracellular space	Cl⁻ (Ca²⁺-activated)
IP₃R	SR membrane	SR lumen → Cytosol	Ca²⁺ (via IP₃)
EAAT1/2	Astrocyte membrane	Synaptic cleft → Astrocyte cytosol	Glutamate + 2 Na⁺ + H⁺ in, K⁺ out
EAAT3	Neuron membrane	Synaptic cleft → Neuron cytosol	Glutamate + 2 Na⁺ + H⁺ in, K⁺ out
SNAT1/2	Neuron membrane	Extracellular → Neuron cytosol	Glutamine + Na⁺
SNAT3/5	Astrocyte membrane	Bidirectional (mostly cytosol → out)	Glutamine + Na⁺ / H⁺ exchanger
Na⁺/K⁺ ATPase	Neuron membrane	3 Na⁺ out / 2 K⁺ in (cyclic)	Maintains gradient (ATP-dependent)