Synaptic and Neuromuscular Transmission Flashcards
Synpase
. Specialized connection btw neuron and receptor cell
. Presynaptic and postsynaptic regions and a space (synaptic cleft)
Electrical synapses
. Cell membrane of presynaptic and postsynaptic cells physically close in association
. APs transmitted directly via gap junctions
. No synaptic cleft
. NOT COMMON IN MAMMALS
Chemical synpase
. Electrical signal transmitted indirectly across cleft via chemical neurotransmitter
. STANDARD IN PEOPLE
Chemical synapse mechanism
. AP in presynaptic cell causes fusion of vesicles w/ membrane and release of neurotransmitter (NT) into cleft
. NT diffuses across cleft and binds to receptors on postsynaptic membrane
. Results in opening or closing of ion channel
. Change in ion channel activity causes graded potentials in postsynaptic cell that depolarize or hyperpolarize cell
. Delay seen btw pre and post cells due to chemicals having to diffuse and bind
Things that could happen to neurotransmitter floating around synaptic cleft
. Reuptake: taken up by presynaptic cell for recycling
. Diffusion: floats out of cleft
. Degradation: enzymes present in and around synapse degrade it
. Makes it so signal is present for a very short time in absence of further stimulation
Summation of signals
EPSPs and IPSPs need to sum together to reach threshold for firing APs
Integration of signals
. Input from multiple sources is combined through process of summation of large number of excitatory and inhibitory signals
Convergence of signals
Effect of large number of presynaptic neurons impinging on single postsynaptic neurons
. Most neurons receive input from many other neurons
Divergence of signals
. Single presynaptic neuron impinging on more than 1 postsynaptic neuron
. Normally is only 1 axon, but it may have collaterals that output onto a number of postsynaptic neurons
Physiological modulation
. Normal regulation of synaptic transmission
. Postsynaptic potentials can be variable in magnitude due to the changes in presynaptic and sometimes postsynaptic factors
. Much more common is presynaptic modulation
Presynaptic facilitation or inhibition is most often due to ____
. Changes in presynaptic Ca concentration that inc. or dec. vesicle fusion
Presynaptic facilitation
. Excitatory neurons impinging on presynaptic terminal or axon
. Inc. amt neurotransmitter released from presynaptic terminal
Presynaptic inhibition
Inhibitory neuron impinging on presynaptic terminal or axon
. Dec. amt of NT released from presynaptic terminal
. Impinging neuron has no direct effect on firing on postsynaptic neuron that is interacting with the neuron it is impinging on
. Only indirect effect by inhibiting the neuron it is impinging so there is no transmission to the final postsynaptic neuron
Modulation of synaptic transmission by drugs
. Every step in normal process can be enhanced or inhibited by drugs
. Most important sites of action for neurologically active drugs is synapses
How tetanus bacillus toxin interferes w/ motor neurons
. Stops inhibitory motor neurons of skeletal muscle so they are in constant activation
. Releases inhibitory transmitters from interneurons inn spinal cord causing no presynaptic transmission
. Causes proteolysis of SNARE proteins involved in fusion of synaptic vesicles to presynaptic plasma membrane
What kind of neuron excites skeletal muscle?
Alpha-motor neuron
Neuromuscular junction
. Motor axon terminals embedded in grooves in skeletal muscle fiber’s surface
. ACh-containing vesicles concentrated in active zone in synaptic terminal
. Active zones located over junctional folds in motor end-plate
Neurotransmitter in neuromuscular junction
. ACh
. Synthesized from choline and acetyl CoA via choline acetyltransferase (ChAT)
. Stored in vesicles in presynaptic terminal
. Found in active zone directly opposite moor end-plate
Exocytosis of ACh vesicles process
. Depolarization causes inc. in intracellular Ca via voltage-gated channels
. Inc. in Ca culminates in ACh release
. More intracellular Ca, more vesicles that fuse so more ACh released
Motor end-plate
. Specialized region of sarcolemma
. High contraction of ACh receptors (nicotinic cholinergic receptors)
. ACh-induced excitation of muscle fiber only happens here
. Have junctional folds to inc. surface area
Nicotinic cholinergic receptors
. Ligand-gated
. Several subunit form a pore
. 2 molecules ACh bind to alpha-subunits exposed on membrane surface
. Opens pore in portion of receptor embedded in lipid bilayer
. Na and K ions flow through open channel down electrochemical gradients
End plate potential (EPP)
. Channels opening in response to normal ACh release allow current to flow and depolarize end plate
Characteristics of EPP
. Graded
. Generated by mixed cation channel that is art of same protein as nicotinic receptors
. Conducts NA better than K so the equilibrium potential is near 0 mV
Effect of EPP
. Causes postsynaptic membrane potential to move towards 0mV
. Exhibits excremental conduction
. Augmented in amplitude and duration when rate of ACh degradation is dec. from drugs (negostigmine)
Margin of safety in EPPS
. Single neuronal AP can initiate postsynaptic (muscle) AP
. EPP can depolarize muscle by 50 mV, but only has to depolarize it 30 mV to reach threshold
. Beneficial in long term repetitive stimulation of presynaptic neuron as ACh release per AP declines from depletion
. Magnitude of EPP dec., but is still enough to make postsynaptic AP due to this safety
Relationship btw amplitude of EPP and muscle AP
. Normal 1:1 correspondence btw motor neuron AP and skeletal muscle AP
. Means that decision to excite muscular fiber is in CNS and is not modulated at neuromuscular synapse
Miniature end-plate potentials (MEPPs)
. At rest (no neuronal APs), single vesicles spontaneously fuse and release ACh into synaptic cleft
. Causes small depolarization (o.4 mV) of end plate
. Does not result in AP
. Occurs due to basal level of Ca in synaptic terminal
. Involved in trophies maintenance of functional integrity of neuromuscular junction
Modulation of neurotransmitter release in neuromuscular junction
. ACh amount released depends on available of ACh in immediate vesicle store and Ca concentration in synaptic terminal
. Level o dCa and ACh depends on amount of time btw successive depolarizations of terminal
. Minimum time needed for Ca and ACh to recover to pre-stimulation levels n
How alteration in ACh release effect neuromuscular transmissions
. Mild to moderate ACh alterations don’t affect normal muscle function due to EPP safety margin
. Facilitation of ACh release will inc. size of EPP, but EPP normally exceeds threshold for AP anyway
. Take large depression of ACh release due to large safety
. Comes into play in disorders that decrease safety and ACh and Ca levels matter more
Lambert-EatonSyndrome
. Complication of cancers, esp small-cell carcinoma in lung
. Weakness from dec. ACh release in motor nn from dec. Ca channels
. Patient blood has high antibodies to Ca channels causing destruction of them
. Immunosuppressants relieves symptoms
Ca-triggered vesicle fusion mechanism
. SNARE proteins on synaptic vesicle and plasma membrane complex together and fuse
. Ca binds to synaptotagmin on vesicle membrane
. Cytoplasmic region of protein inserts into plasma membrane and catalyzes membrane fusion
Structure of SNARE complex
. Vesicular synaptobrevin form helical complex w/ syntaxin and SNAP-25
Botulism
. Group of toxins from Clostridium botulinum bacteria
. Causes muscle weakness and paralysis by interfering w/ ACh release
. Can cause respiratory failure
. Degrades SNARE so it is preferential to ACh and skeletal muscle
. Can be some smooth muscle dysfunction as well
Myasthenia Gravis
. Unable to maintain prolonged contraction of skeletal muscles
. Starts in eyelids
. Patients have antibodies to nicotinic receptor on skeletal muscles from autoimmune response
. Motor neurons less likely to cause postsynaptic muscle cells to reach threshold
. Treatment: cholinesterase inhibitors
What occurs in skeletal muscle if there is an insufficient supply of ATP
. Myosin can’t dissociate from actin, cross bridge remains intact
T/F rigor mortis represents maximal contraction
F
Ca-ATPase role in skeletal muscle contraction
. In sarcoplasmic reticulum
. Actively transports Ca ions into sarcoplasmic reticulum which lowers free Ca concentration
. This terminates contraction and allows muscle fiber to relax
. ATP hydrolysis provides energy to transport Ca
What determines maximal muscle contraction velocity?
. Rate of ATP hydrolysis determined rate of cross-bridge cycling
WHat is one of the most important factors influencing speed of cross-bridge cycling and sarcomere shortening?
. Isoform of MHC expressed in muscle fiber
Which type of muscle fibers have an isoform of myosin ATPase that splits ATP to ADP and P quickly?
Fast-twitch muscle fibers
T/F there is only one neuromuscular junction per muscle fiber
T
Where is the neuromuscular junction located in muscle fiber?
Near the middle of fiber so AP can spread equally to both sides
The amount of ACh that is normally released during AP opens ____ ion channels in motor end plate?
400,000
ACh receptors
. On postsynaptic membrane
. Nicotinic
. Ligand-gated, cation-selective (Na, K, Ca)
. Open upon ACh binding
Acetylcholinesterase
. Degrades ACh
. Located in postsynaptic membrane
. Choline taken back into presynaptic motor nerve terminal for resynthesis of ACh
Transmission at neuromuscular junction
. AP generated in motor neuron
. Depolarization of neuron axon terminal opens voltage-gated Ca channels, Ca moves into acorn terminal
. Exocytosis of ACh-containing vesicles (# dependent on Ca concentration in n. Terminal
. ACh diffuses to ACh receptors on motor end-plate of muscle membrane (in junctional folds of sarcolemma)
. ACh binds to receptor causing large cationic influx (mostly Na) and small K efflux generating depolarizing EPP
. EPP generate AP in muscle membrane
. Acetylcholinesterase breaks down remaining ACh in neuromuscular junction to prevent continued contraction
SKeletal muscle resting membrane potential
. potential has large contribution to Cl conductance along with K
. Value is more negative in muscle than neurons
Skeletal muscle action potential
. EPP produces local inward current flow at motor end plate
. Initiates AP in muscle membrane that propagates over surface of muscle fiber
. Na current through voltage-aged Na channels generates upstroke of AP in muscle membrane
. K current generates repolarization of muscle membrane
How black widow spider venom alters release of ACh
. Causes explosive release of ACh
How clostridium botulinum toxin alters ACh release?
. Blocks ACh release
How lambert-Eaton syndrome alters release of ACh
. Self-producing antibodies to Ca channels diminish Ca influx into presynaptic terminal during AP
. Reduces ACh release
How curare bloack ACh receptor site
Reversible binds to ACh receptor sites
How myasthenia Gravis blocks ACh receptors
Self-produced antibodies that inactivate ACh receptor sites
How organophosphates prevent inactivation of ACh
. Irreversibly inhibits acetylcholinesterase
Excitation-contraction coupling
. Series of events linking electrical phenomena occurring in plasma membrane to cell shortening that causes muscle contraction
. Delay (latent period) btw electrical signal and mechanical response represent excitation-contraction coupling
Transverse tubules
. Invaginations in sarcolemma
. Conduct AP rapidly to center of cell
. Results in homogenously synchronic muscle contraction
. Flanked by terminal cisternae
Terminal cisternae
. Sack-like structures
. Store and release Ca for contraction
.
Longitudinal portion of sarcoplasmic reticulum in skeletal muscle significance
Forms network where Ca-ATPase-mediated Ca reuptake takes place
Role of Ca in skeletal muscle contraction
. SR is sole source of Ca
. Needed for cross-bridging
. As long as Ca and ATP are available, cross-bridge cycling continues
. When SR removes Ca from muscle cytoplasm relaxation occurs
Slow oxidative fibers
.red . Oxidative phosphorylation primary ATP source . Many mitochondria . High myoglobin content . Low glycogen content . Slow rate of fatigue . Slow contraction velocity . Small fiber diameter . Small motor unit size . Small size of motor neuron innervating fiber
Fast oxidative glycolytic fibers
. Red
. Oxidative phosphorylation primary source of ATP
. Many mitochondria
. High myoglobin content
. Intermediate glycogen, rate of fatigue, contraction velocity, fiber diameter, motor unit size, and size of motor neuron innervating fiber
Fast glycolytic muscle fibers
. Glycolysis primary source ATP . Few mitochondria . Low myoglobin . High glycogen . Fast rate of fatigue . Fast contraction velocity . Large fiber diameter, motor unit size, and size of motor neuron innervating fiber
Muscle tension
. Force exerting on an object by a contracting muscle
Types of muscular contraction
. Isotonic
. Isometric
. Lengthening
Isotonic contraction
. Muscle tension remains constant as muscle length changes
. Occurs when muscle shortens causing load to be moved
. Also called concentric contraction
. Muscle tension is greater than opposing load
Isometric contraction
. Static
. Muscle is prevented from shortening so tension develops at constant muscle length
. Occurs when muscle supports load in constant position (doesn’t move)
. Muscle tension is equal to the opposing lead
Lengthening contraction
. Load pulls muscle to longer length in spite of opposing force being produced by cross bridges
. Eccentric contraction
. Lengthening of muscle fibers is consequence of external force being applied
. Muscle tension less than opposing load
Latent period in skeletal muscle
. AP in skeletal muscle lasts less than 5 ms
. Onset of contractile response lags behind AP due to entire process of excitation-contraction coupling must take place before cross-bridging begins
Summation of skeletal muscle contractions
. Ca removal from cytoplasm takes time
. Inc. in muscle tension from successive APs during phase of mechanical activity
. Tension is summated, not voltage
. APs don’t summate, muscular contractions do
Maximal force of contraction is reached with what kind of tetanus?
Fused tetanus
Tetanus mechanism
. Sustained contraction where individual twitches aren’t distinguishable from each other
. Single twitch cytosolic Ca levels remain elevated after AP terminates, 2nd AP excites muscle during this period and more Ca released further inc. Ca concentration
. Resulted in larger muscle tension
T/F Each AP always produces same amount of SE release, which is the max amount
T, Ca release from SR is not regulated
How maximal muscle tension occurs
. Single AP doesn’t produce it
. When APs come at high frequency, the basal Ca concentration rises, inc. total cytosolic Ca concentration during summation
. If cytoplasmic Ca concentration remains high, maximal tension will develop
T/F fast glycolytic fibers tetanize at higher frequency than slow fibers
T
What is the optimum muscle length?
Resting length
What happens when muscles are overstretched?
. No overlap btw actin and myosin
. Cross-bridging can’t occur
What happens when muscles are overshortened?
. Actin and myosin physically overlap
. Interferes w/ cross-bridge formation
Force-velocity relationship
. Contraction properties depend on amount of load
. Smaller load: larger shortening, faster muscle contractions
. At lower loads, muscle tension generates isotonic shortenings
. When load exceeds tension, lengthening contraction occurs
Motor units
. Motor neuron plus muscle fibers it innervates
.When AP happens, all muscle fibers in motor unit contract
. Muscle fibers of unit are always the same type
. Motor unit size depends on muscle function
. Fine motor control: smaller units
Motor unit recruitment
. Inc. number of motor units that are active in a muscle
. Determines total tension that a muscle can develop
. Motor units w/ lowest threshold activate first, then recruitment progressively add motor units
. Results in greater force production
Most excitable motor units are what kind of fibers?
Slow oxidative fibers
. Found in fine-movement muscles and in muscles used for continuous movements
Least excitable motor unit muscle fiber type?
Fast glycolytic fibers
. Activated during high intensity activity when quick bursts of power are needed
Size principle with skeletal muscle
. Small motor units activated first
. Progresses to more difficult to excite, more powerful large motor units
. Small units: small motor neurons, conduct APs slowly and excite fewer fibers that are slow twitch type
. Large units: large motor neurons, conduct APs rapidly and excite many fibers that are fast twitch type
Graded force production in skeletal muscle is primarily determined by ____
. AP frequency w/ summation of contractions
. Recruitment of motor units
Number of fibers per motor units determines what relationship?
. Frequency-tension relationship (AP frequency w/ summation)
Number of active muscle fibers determines ___
Tension developed by each individual fiber
Number of active motor units (recruitment) determines that relationship?
Length-tension relationship (fiber length)
Sources of energy for skeletal muscle
. Phosphocreatine: enzyme creatine phosphotransferase tranfers P to ATP reforming ATP
. Glycogen: degraded to pyruvate then lactate for anaerobic glycolysis
. Pyruvate: w/ oxygen, enters TCA for oxidative phosphorylation
Muscle fatigue
. Process to replenish energy stores takes energy
. Muscle consumes O at inc. rate (O2 debt) for some time after activity has stopped to replenish energy stores
. When muscle repeatedly stimulated, the max tension produced dec. (fatigue)
. Dec. shortening velocity
. Slower rate of relaxation
Growth of skeletal muscle
. Growth is adding new myofibrils w/in a cell, formation of new cells, or adding more sarcomeres in series as muscle cells lengthen along w/ skeletal growth
Muscle hypertrophy
. Addition of myofibrils inc. muscle mass
. Adds sarcomeres parallel
. Inc. size of individual muscle fibers inc. force
. Short duration high intensity inc. fast glycolytic fibers
. Low intensity long duration produces changes in slow oxidative and fast oxidative-glycolytic fibers, but only limited hypertrophy
. Muscle fibers in men are thicker and larger from androgenic steroid hormones in higher concentrations
Muscle atrophy
. Disuse
. Enervation: motor neurons destroyed
Muscular dystrophy
. Structural defects of cytoskeletal proteins can lead to group of muscle disorders
. Characterized by weakness and muscle mass loss
Muscle hyperplasia
. Number of muscle fibers inc.
. Skeletal m. Has limited ability to form new fibers
. Happen from differentiation of satellite cells present in tissues
. Can occur as result of high volume moderate intensity weightlifting protocol used by some bodybuilders
. Overall contribution to muscle size and strength is minimal
Muscle postnatal growth
. Muscle growth in kidneys occurs by lengthening and hypertrophy
External causes of muscle damage
. Contusions/crushing
. Laceration
. Extreme heat or cold
Internal causes of muscle damage
.muscle tears: accompanied by bleeding into muscle belly
. Extreme/unaccustomed exercise: due to eccentric contraction, high force generation and overstretch of sarcomeres
. Diseases: cause inflammation
Muscle fiber necrosis
. Occurs with damage to sarcolemma
. Excessive amounts of Ca enter into muscle from interstitial fluid
. Ca ions activate proteases that start to digest structural proteins
. Accompanied by release of growth factors and cytokines that stimulate immune system
. Significant swelling and edema
. WBCs enter necrotic area, continue the degradation of damaged structures and remove debris
Muscle regeneration
. Initial step: satellite cells active
. Move to necrotic region and differentiate into myoblasts
. Myoblasts differentiate into myotubes
. Leads to regeneration and repair of damaged tissue through muscle protein synthesis
Muscle injury during exercise
. Most injuries from eccentric contraction ( can occur in overstretched while unstimulated m.)
. Site of injury often at myotendinous junction
. Mechanical disruption of sarcolemma or in sarcomeres, assoc. w/ rise in Ca
. Lack of training and fatigue are most common predisposing factors
Delayed onset muscle soreness (DOMS)
. Significant muscle soreness that peaks 24-48 hours after exercise
. Degree of discomfort depends on intensity and duration of exercise
. Experienced after unaccustomed exercise
. Most commonly associated w/ eccentric contractions
. Affects fast-twitch fibers more
Observed changes in muscle during injury
. Osmotic pressure changes causing swelling
. Damage to sarcolemma
. Efflux from muscle of enzymes (esp creatine kinase) and myoglobin
. Altered ER function w/ poor control of cytosolic Ca concentration
Cause of delayed soreness
. From acute inflammation and cellular swelling
. Processes activated by rise in cytosolic Ca
