What are the structural components of a chemical synapse?
Axon terminals
Synapses
Dendrites
Axon terminals are packed with _________________
Synaptic vesicles
What are postsynaptic densities?
Accumulations of receptors on the postsynaptic membrane of the dendrite
What are electrical synapses?
Gap junctions
Synaptic cleft of chemical vs electrical synapses
Electrical synapses smaller than chemical synapses
What kind of synapses are found in cardiac muscle and some types of smooth muscle (uterus and bladder)
Electrical synapses
Peptide neurotransmitters are produced in the _______________
Cell body
Non-peptide neurotransmitters are produced in the _______________
Axon terminal
Role of microtubules in neuron
Create a highway for peptide neurotransmitters to reach axon terminal
Vesicle and peptide neurotransmitter precursors and enzymes are synthesized in the ________________ (organelle) and released from the ______________ (organelle)
Endoplasmic reticulum
Golgi
What is the role of calcium in presynaptic vesicle release?
Calcium controls vesicle fusion and mobilization of synaptic vesicles
________________ controls vesicle fusion and mobilization of synaptic vesicles
Calcium
Role of synapsin in presynaptic vesicle release
Restraint (non-phosphorylated)
Mobilization (phosphorylated)
What is restraint?
Non-phosphorylated synapsins bind vesicles to actin filaments
Synapsins are substrates for ___________________ and _________________
cAMP-dependent protein kinase
Calcium/calmodulin-dependent protein kinase
What is mobilization?
Phosphorylated synapsins release vesicles from actin filaments
When do synapsins become phosphorylated?
With calcium entry
Rab proteins bind _________________
GTP
______________ targets the vesicles that have already been liberated from the actin filament to the active zones of the presynaptic membrane
Rab/GTP complex
Vesicle protein, synaptobrevin (VAMP), interacts with membrane proteins to form a ________________ and do what?
SNARE complex
Dock the vesicle to the presynaptic membrane
Role of munc18 in presynaptic vesicle release
For exocytosis of synaptic vesicles
Elimination of munc18 prevents ______________
Vesicle fusion
Munc18 binds to syntaxin before/after synaptobrevin binds
Before
______________ targets and cleaves VAMP
Tetanus
______________ cleave SNAP-25, VAMP, and syntaxin
Botulinum toxins
What do clostridial neurotoxins do?
Interfere with docking and priming by cleaving SNARE proteins
Examples of clostridial neurotoxins
Tetanus
Botulinum toxins
Alpha-latrotoxin causes…
Massive calcium influx in the neuron which causes massive release of acetylcholine and cholinergic symptoms
What is the role of synaptotagmin in presynaptic vesicle release?
Binds with calcium and is considered a calcium sensor
The binding of calcium to synaptotagmin triggers…
Vehicle fusion
Pore formation
Release of the neurotransmitter
What is the final step in neurotransmitter release cycle?
Recycling of the vesicles and disassembling the SNARE complex
What is the role of NSF in presynaptic vesicle release?
Binds to SNARE complex and unravels it
What are the mechanisms of neurotransmitter termination?
Diffusion
Enzymatic degradation
Reuptake
Glutamate transporters use _______________ and transporter for all other neurotransmitters use __________________
Na/K exchange
Na and Cl cotransport
________________ transporters have no chloride dependence
Glutamate
List the vesicular uptake transporters
VMAT1 and VMAT 2 (for monoamines)
VGAT (for GABA)
VAChT (for acetylcholine)
What is the role of vesicular uptake transporters?
Get the neurotransmitters into synaptic vesicles
In neurotransmitter uptake, plasma membrane transporters use the __________ gradient and vesicle transporters use the ___________ gradient
Na+
H+
Acetylcholine is degraded into ____________ and _______________ by _________________
Acetate
Choline
Acetylcholinesterase
Serotonin is derived from which amino acid? This amino acid is a precursor to which molecule?
Tryptophan
Melatonin
What are the steps of getting epinephrine from tyrosine?
Tyrosine hydroxylase can be blocked by ________________
Metyrosine
What is the function of VMAT?
Transport channel that transports monoamine neurotransmitters into vesicles
VMAT can be blocked by _______________
Resperpine
______________ and _______________ terminate neurotransmitter action
NET
DAT
What are NET and DAT?
NET: norepinephrine transporter
DAT: dopamine transporter
Where does dopamine --> norepinephrine take place?
In the vesicle
NET and DAT are blocked by ________________
Cocaine
NET and DAT action can be reversed by _________________. What is the new action after reversal?
Amphetamine
NE and DA pumped out of neuron
What are the three catecholamines?
Epinephrine
Norepinephrine
Dopamine
What are the four monoamines?
Epinephrine
Norepinephrine
Dopamine
Serotonin
Calcium is needed for neurotransmitter release, what does it do?
Mobilizes vesicles
Creates fusion pore
What is the role of astrocytes in synaptic transmission?
Hep with synthesis of some neurotransmitters
What is the cause of Lambert-Eaton Myasthenic Syndrome (LEMS)?
Antibodies against voltage gated calcium channels in presynaptic terminals cause absence of calcium so no neurotransmitter release (no acetylcholine = muscle weakness)
What kind of receptors are found at the neuromuscular junction?
Ionotropic receptors are ___________-gated which means the channel opens when…
Ligand
Ligand binds
Ligand-gated channels have ___________ subunits
5
Ligand-gated channels vs gap junctions structure
Gap junctions formed by hemichannels and have 6 subunits
Ligand-gated channels vs voltage-gated channels structure
Voltage-gated channels have 4 subunits
What is a metabotropic receptor?
Receptor is a separate protein from the ion channel
Activates a G-protein
G-protein coupled receptors have _____ subunits
1
Active state of a G-protein has ________ bound
GTP
G protein is inactivated when…
GTP hydrolyzed to GDP
Effects of Gs, Gi, and Gq
Gs: increases cAMP
Gi: decreases cAMP
Gq: increases IP3 and DAG
Examples of metabotropic receptors
GPCRs
Receptor tyrosine kinases (RTKs)
Examples of ionotropic receptors
Neuromuscular junction
Receptor tyrosine kinases lack…
Intrinsic kinase domains, but borrow from kinases not part of the receptor
Ionotropic vs. metabotropic receptors: speed
Metabotropic much slower
Ionotropic vs. metabotropic receptors: area of action
Ionotropic: local action
Metabotropic: widespread action
Ionotropic vs. metabotropic receptors: neuronal firing
Ionotropic: excites or inhibits neuronal firing
Metabotropic: usually does not lead directly to action potentials
Why are sweat glands an exception for sympathetic innervation?
Sweat glands have muscarinic receptors in postsynaptic sympathetic fiber
Nicotinic vs muscarinic acetylcholine receptors
Nicotinic: ligand-gated ion channels, ionotropic, fast EPSP
Muscarinic: GPCR, metabotropic, slow EPSP
Both nicotinic and muscarinic receptors ___________ outward K+ current by ____________ K+ channels, thus encouraging __________________
Decrease
Closing
Depolarization
Which type of receptors have more widespread action, ionotropic or metabotropic?
Metabotropic
_________________ receptors usually do not lead directly to action potentials
Metabotropic
What is the exception to sympathetic innervation?
Sweat glands have muscarinic receptors, but are sympathetic
Acetylcholine leads to slow/fast EPSPs through ______________ receptors and slow/fast EPSPs through ________________ receptors
Fast
Ionotropic
Slow
Metabotropic
What do ionotropic and metabotropic receptors do to cause depolarization?
Decrease outward K+ current by closing K+ channels (open at rest)
Metabotropic receptors close ___________ channels to activate depolarization
M-type K+
Nicotinic receptors are ________________ and muscarinic receptors are _________________
Ionotropic
Metabotropic
Examples of metabotropic channels
K+ channels
Heart
GIRK
Serotonin receptors are AKA _________________
5-HT receptors
What kind of receptors are serotonin receptors?
Both GPCR and ligand-gated
5-HT1 and 5-HT2 receptors are which type of receptor and are they inhibitory/excitatory?
Both GPCR
5-HT1: inhibitory
5-HT2: excitatory
5-HT3 receptors are which type of receptors and are they inhibitory/excitatory?
Ligand-gated channel
Excitatory
What antibody is measured to diagnose myasthenia gravis?
AchR-ab
The myasthenia gravis antibody is _________________ and it acts against ________________
AChR-ab
Nicotinic ACh receptors on the postsynaptic terminal
The LEMS antibody acts against _______________
Voltage-gated calcium channels in the presynaptic terminal
What is the pathophysiology behind myasthenia gravis?
Motoneurons produce ACh normally but antibodies bind to the ACh receptors, so ACh can’t bind and no depolarization happens
_______________ is an acetylcholinesterase inhibitor that is used to improve muscle strength in myasthenia gravis
Pyridostigmine
In myasthenia gravis, the defect lies in the ______________ and in LEMS, the defect lies in the _______________
ACh receptors
Calcium uptake by motoneurons
Electrophysiology of Neurons – Dr. Pong
Action potential in a spherical cell vs. action potential in a cylinder
AP in a cylinder is able to propagate
What happens to the amplitude of the action potential as it moves down the axon?
Decays
Decay of the action potential as it propagates down axon is determined by:
Membrane resistance
Membrane capacitance
Internal resistance
Membrane length constant, λ, is the…
Distance that a graded potential will travel along an axon
Membrane length constant (λ) relationship with resistance
λ is proportional to square root of (membrane resistance ÷ internal resistance)
How does nerve diameter affect conduction velocity of an AP?
Larger diameter = faster conduction
What is membrane time constant, τ? What is the equation?
Time required to change the membrane
τ = membrane resistance x membrane capacitance
What type of axon has the fastest conduction velocity of an AP?
Axon with:
High resistance to charge loss (high length constant)
Ease in charging the membrane (low time constant)
How can you increase conduction velocity of an AP?
Increasing nerve diameter and having myelination
What does myelin do in terms of membrane resistance and capacitance?
Increases membrane resistance
Decreases membrane capacitance
What are the advantages of saltatory conduction?
High speed and low metabolism cost
Nodes of Ranvier contain ________________ in high density
Voltage-gated Na+ channels
In the periphery, APs are shut off by the inactivation of the ______ channel and a large outward ______ current. Voltage-gated K+ channels are common/uncommon.
Na+
K+
Uncommon
In both the CNS and periphery, high densities of ______________ are located beneath the myelin sheath. What happens in demyelinating diseases?
K+ channels
K+ channels exposed and slow down AP
What are the ways an EPSP can be created?
Positive ions entering the cell
Negative ions leaving the cell
What are the ways an IPSP can be created?
Positive ions leaving the cell
Negative ions entering the cell
What effect does hyperkalemia have on action potential generation?
Depolarized membrane potential and keeps AP generation from occurring since inactivation gate cannot close
What effect does hypokalemia have on action potential generation?
Makes K+ leave the cell faster and hyperpolarized the membrane, so keeps you away from reaching AP threshold
How can serotonin have both an excitatory and inhibitory postsynaptic effect? What is an example of one that is inhibitory?
Has both cation channels (excitatory) and GPCR (excitatory or inhibitory)
GPCR can cause K+ channels to open, K+ leaves, leads to hyperpolarization (inhibitory)
What is multiple sclerosis caused by?
Loss of myelination results in decreased conduction speed of Aps
What effect does hypercalcemia have on action potential generation?
Ca blocks voltage-gated Na+ channels which makes cell less excitable
What effect does hypoxia have on action potential generation?
No oxygen, no ATP, Na+/K+ pump does not work without ATP, no AP
What effect does hypoxia have on cells?
Na+/K+ pump doesn’t work, Na+ stays in cell and draws water into cell (swells)
Physiology of Sensation and Pain – Dr. Pong
What are the four qualities of pain sensation?
Modality
Location
Intensity
Duration/frequency
What is a receptive field?
The area that is sensitive to the stimuli
Small receptive field vs. large receptive field
Large receptive fields have inputs from multiple neurons
Contrast the organization of muscle activation (spinal motoneuron to muscle) with the organization of pain sensation (nerve ending to spinothalamic relay neuron)
Sensory info comes into the spinal cord via the ____________ horn and motor info comes out of the spinal cord via the ______________ horn
Anterior/ventral
Posterior/dorsal
What is a receptor potential?
Membrane potentials at free nerve endings
Can receptor potentials become action potentials?
Yes, membrane potentials summate and if threshold is reached --> AP
________________ channels open to specific stimuli in free nerve endings and cause receptor potentials
Transient receptor potential (TRP)
What are the types of nociceptors?
Temperature
Mechanical
Polymodal
Silent
Thermal nociceptors: diameter, myelination, types of fibers, speed
Small diameter
Thinly myelinated
A-delta fibers
Fast
Mechanical nociceptors: what they sense, types of fibers
Sense intense pressure to skin
A- delta fibers
Polymodal nociceptors: what they sense, diameter, myelination, types of fibers, speed
Mechanical, chemical, thermal stimuli
Small diameter
Nonmyelinated
C fibers
Slow
Silent nociceptors are found in the _____________ and are normally activated/not activated by noxious stimuli
Viscera
Not activated
When can silent nociceptors be activated and why?
Inflammation, reduces firing threshold
How can you affect the intensity or duration of pain sensation?
Involve other nociceptors and sensory receptors
A-delta fibers vs. C fibers type of pain caused
A-delta fibers: initial, sharp pain
C fibers: later, dull, achy pain
How do chemical mediators affect sensitivity of nociceptors?
Can either activate nociceptors or sensitize them
Examples of chemical mediators that can sensitize nociceptors
Prostaglandins
Bradykinin
Bradykinin effect on nociceptors
Activates A-delta fibers and C fibers
Mechanism of NSAIDs
Block cyclooxygenase (generate prostaglandins)
Somatosensory pathway of neurons in the anterolateral system (pain, temp)
First order neuron from receptor to spinal cord
First order neuron synapses with second order neuron in spinal cord
Second order neuron crosses over to other side and ascends up to thalamus
What is the mechanism of referred pain of visceral origin?
Fibers of different origin cross in the dorsal horn leading to incorrect localization of pain
(ex: heart attack, arm pain)
_________________ is the idea that pain transmission can be disrupted with non-noxious stimulation
Gate control theory of pain
What are the 4 parts of the upper limb?
Shoulder girdle (scapula and clavicle)
Arm (humerus)
Forearm (radius and ulna)
Hand
What is the only bony connection between the upper limb and body?
Joint between clavicle and sternum
Vasculature of the arm from heart to fingers
Subclavian artery --> (passes first rib) --> axillary artery --> (passes teres major) --> brachial artery --> (passes elbow and splits) --> radial artery and ulnar artery --> form superficial palmar arch and deep palmar arch in hand --> branches to fingers
Shoulder vasculature (scapular anastomosis)
Dorsal scapular artery
Suprascapular artery
Circumflex scapular artery
What are mammary glands?
Modified sweat glands
What is the axillary tail of mammary glands?
Extends into the armpit and breast cancer metastasizes through this
________________ act as walls to separate breast into 15-20 lobes
Suspensory ligaments
Arteries that supply mammary glands
Internal thoracic artery
Lateral thoracic artery
Thoracoacromial artery
Branches of intercostal arteries
Describe the lymphatic drainage of the mammary glands
75% drains to axillary nodes (from lateral breast)
25% drains to parasternal nodes (from medial breast)
Pectoralis major origins
Clavicular head
Sternocostal head
Costal cartilages 1-6
Pectoralis major insertions
Intertubercular sulcus of humerus (bicipital groove)
Pectoralis major innervation
Lateral and medial pectoral nerves
Pectoralis major actions
Medially rotates arm
Adducts arm
Pectoralis minor insertions
Coracoid process of scapula
Pectoralis minor origins
Ribs 3-5
Pectoralis minor innervation
Medial pectoral nerve
Pectoralis minor actions
Depresses scapula
Elevated ribs for deep inspiration
Subclavius insertion
Clavicle
Subclavius origin
First costal cartilage
Subclavius innervation
Nerve to subclavius
Subclavius actions
Depresses and anchors clavicle
Serratus anterior insertions
Medial border of scapula
Serratus anterior origins
Ribs 1-8
Serratus anterior innervation
Long thoracic nerve
Serratus anterior actions
Rotates scapula
Draws scapula forward
Anchors scapula against thoracic wall
Winged scapula results from damage to _______________
Long thoracic nerve
Where is clavipectoral fascia located?
Surrounds pectoralis minor and is in between of pectoralis major and minor
What are the structures that pierce the clavipectoral fascia?
Cephalic vein
Thoracoacromial artery
Lateral pectoral nerve
Clavipectoral fascia protects…
Nerves of brachial plexus and axillary vessels
What are the contents of the clavipectoral triangle?
Cephalic vein
Tip of coracoid process of scapula
What are the borders of the clavipectoral triangle?
Deltoid
Pectoralis major
Clavicle
Clavipectoral triangle is protected by ______________
Pectoral fascia
Clavipectoral triangle is AKA _______________
Deltopectoral triangle
__________________ receive lymph from humeral, subscapular, and pectoral nodes
Central nodes
_________________ drain upper limb
Humeral nodes
_________________ drain posterior wall of axilla
Subscapular (posterior) nodes
_________________ drain anterior wall of axilla, including lateral breast
Pectoral (anterior) nodes
_________________ receive lymph from central nodes
Apical nodes
Right lymphatic duct drains lymph from which parts of body?
Right side of head, neck, trunk, and right arm
Thoracic duct drains lymph from which parts of body?
Left side of head and neck
Left arm
Abdomen
Lower extremities
What are the boundaries of the axilla?
Anterior wall
Posterior wall
Medial wall
Lateral wall
What is the posterior wall of the axilla comprised of?
Scapula
Subscapularis
Insertion of latissimus dorsi
Teres major
What is the anterior wall of the axilla comprised of?
Pectoralis major
Pectoralis minor
What is the medial wall of the axilla comprised of?
Upper 4-5 ribs
Intercostal muscles
Serratus anterior
What is the lateral wall of the axilla comprised of?
Humerus
Axillary artery is divided into three parts in reference to which muscle?
Pectoralis minor
The first part of the axillary artery begins at the ______________ and ends at the ________________
Border of clavicle
Pectoralis minor muscle
The second part of the axillary artery is located…
Under the pectoralis minor
The third part of the axillary artery begins ______________ and ends ________________
After pectoralis minor
Lower border of teres major
What are the branches off the first part of the axillary artery?
Superior thoracic artery
What are the branches off the second part of the axillary artery?
Thoracoacromial trunk
Lateral thoracic artery
What are the branches off the third part of the axillary artery?
Subscapular artery
Anterior circumflex humeral artery
Posterior circumflex humeral artery
What is the artery that supplies serratus anterior?
Lateral thoracic artery
The brachial plexus is formed by the ___________ rami of ____________
Ventral
C5-C8 and T1
What are dermatomes?
Strips of skin innervated by an individual spinal root
Important dermatomes: the nipple is innervated by spinal segment _________, the umbilicus ________, the fingertips _________, and the toes __________
T4
T10
C6-T1
L5-S1
What is a prefixed brachial plexus?
Brachial plexus starts at C4 (normal: C5)
What is a postfixed brachial plexus?
Brachial plexus ends at T2 (normal: T1)
Sections of the brachial plexus: how many roots?
5
Sections of the brachial plexus: how many trunks?
3
Sections of the brachial plexus: how many divisions?
3 anterior
3 posterior
The anterior/posterior divisions of the brachial plexus are in reference to what?
Axillary artery
(anterior to or posterior to)
Sections of the brachial plexus: how many cords?
3
Sections of the brachial plexus: how many branches?
5
The superior trunk of the brachial plexus is made up of…
C5 and C6
The middle trunk of the brachial plexus is made up of…
C7
The inferior trunk of the brachial plexus is made up of…
C8 and T1
Which spinal nerves make up the axillary nerve?
C5-C6
Nicotinic receptors are opened by the endogenous ligand _______________ or by the exogenous ligand _______________
Acetylcholine
Nicotine
Muscarinic receptors are activated by binding the endogenous ligand _______________ or the exogenous ligand _______________
Acetylcholine
Muscarine
What are the substrates of acetylcholinesterase?
Acetylcholine and water
What are the products of acetylcholinesterase?
Acetate and choline
What is the synaptic location of acetylcholinesterase?
In the synapse, attached to postsynaptic membrane
What is the function of acetylcholinesterase?
Degrade ACh
What are the substrates of choline acetyltransferase?
Choline and acetyl-CoA
What are the products of choline acetyltransferase?
Acetylcholine and CoA
What is the synaptic location of choline acetyltransferase?
Inside presynaptic neuron
What is the function of choline acetyltransferase?
Synthesize the neurotransmitter
What are the effects of inhibiting acetylcholinesterase?
Increase in acetylcholine and decrease in choline
How are amino acids precursors to monoamine neurotransmitters?
Amino acids decarboxylased to become monoamine neurotransmitter
Serotonin is AKA ________________
5-hydroxytryptamine (5HT)
What is the role of serotonin in the synapses of the CNS? What about outside of the CNS, crossing the BBB?
Acts as a neurotransmitter
Increases tone (contract) of smooth muscle
List the pathway of biosynthesis of serotonin, including substrates, enzymes, and products
1. Tryptophan hydroxylase turns tryptophan into 5-hydroxytryptophan
2. 5-hydroxytryptophan decarboxylase turns 5-hydroxytryptophan into 5-hydroxytryptamine (5HT, serotonin)
Biosynthesis of serotonin requires which enzyme and which cofactors?
Enzyme: tryptophan hydroxylase
Cofactors: tetrahydrobiopterin and iron
90% of the serotonin in the human body is produced in the _____________
Intestine
What is the primary fuel of the brain? What is the primary fuel for the muscle?
Brain: glucose
Muscle: lipids
What is the cellular location of glycolysis?
Cytosol
What is the cellular location of the citric acid cycle?
Mitochondria matrix
What is the cellular location of the
Mitochondrial inner membrane
How does glucose get into the cell?
Glucose transporters (passive)
Once glucose enters the cell, what traps it in? Why does this trap it in?
Glucose is phosphorylated to glucose-6-phosphate
Glucose-6-phosphate can’t bind to transporter and leave
Phosphorylation of glucose is catalyzed by which enzyme?
Hexokinase
What does hexokinase do?
Adds phosphate to glucose
Phosphorylation of glucose-6-phosphate is catalyzed by which enzyme?
Glucose-6-phosphatase
What does glucose-6-phosphatase do?
Phosphorylates glucose-6-phosphate
Why do we need glucose-6-phosphatase?
Dephosphorylation of glucose-6-phosphate allows glucose to leave cell (liver and kidney)
Glucose 6-P is converted into glucose 1-P by which enzyme?
Phosphoglucomutase
Glucose 6-P is converted into fructose 6-P by which enzyme?
Phosphoglucose isomerase
What is the function of phosphoglucose isomerase?
Glucose-6-phosphate --> fructose-6-phosphate
Which metabolic pathway produces the most ATP?
Oxidative phosphorylation
Which metabolic pathway produces the most NADH?
Citric acid cycle
Glycolysis produces how many ATP and how many NADH?
2 ATP
2 NADH
Citric acid cycle produces how many ATP and how many NADH?
2 ATP
6 NADH
Oxidative phosphorylation produces how many ATP and how many NADH?
32-34 ATP
No NADH
What is the function of glycogen synthase?
G-1-P --> glycogen
What is the function of glucose-6-phosphate dehydrogenase?
