BIO 122 LECTURE 3: NEUROMUSCULAR PHYSIOLOGYJ4R4FFE

I. II. SIGNALLING IN NERVES

NERVE IMPULSE transmission of action potential from the axon hillock to the axon terminals and into the adjacent neuron action potential = all or nothing; does not diminish based on distance from origin action potentials jump from node to node unmyelinated vs. myelinated nerve fibers (voltage-gated Na+ channels are present only at the nodes of Ranvier)

Why action potential jump down axon

1. As charge spreads down an axon, myelination (Schwann cells) prevents ion from leaking out the PM.2. Charge spreads unimpeded until it reaches an unmyelinated section of the axon (node of Ranvier, which is packed with Na+ channels)3. Electrical signals continue to jump down the axon much faster than down an unmyelinated cell.

Normal conduction of myelinated fibers high density voltage-gated Na+ channel at node; saltatory conduction of signalDemyelination of nerve fibers in MS increased Na+ channels along demyelinated axons (multiple sclerosis)

SYNAPSE Charles Sherrington, 1897 specialized intercellular spaces between a neuron and an effector cell or another neuron synaptic transmission vs. axonal transmission presynaptic and postsynaptic terminals

1. Electrical Synapse occurs in gap junction (nexus) present transmission occurs without measurable delay little or no fluctuation in AP (continuous) gap junction are formed exclusively from hexameric pores (connexons) = connect cells with each other for robust electrical coupling functions: metabolic (diffusional exchange); local inhibitory network in CNS2. Chemical Synapse most common synaptic transmission synaptic cleft: 20 to 50 nm time lag occurs AP may fluctuate mediated by NEUROTRANSMITTERS (from terminal bulb of presynaptic axon) synthesized by neuron (1 neuron : 1 transmitter type) present in presynaptic terminals bind to specific receptor on postsynaptic membrane associated with specific mechanisms of deactivation e.g. Ach and Ne no. of vesicles is reduced with: decreased Ca2+ and Na+ in ECF previous depolarization making the AP weaker

Synaptic Transmitter at Neuromuscular Junction (NMJ):Acetylcholine Synthetic and Storage

Quantum: amount of neurotransmitters in one vesicle that determines the minimum size of postsynaptic potential; e.g. Ach = quantal units of 3000 molecules *cholinergic vesicle = ~103 molecules of Ach Quantal release = transmitter is released in quantum (there is a certain amount that is released) miniature EPSPs (mEPSPs) change in the membrane potential of a muscle cell produced by a single quantum mEPSPs EPSP threshold AP to postsynaptic terminal normal neurotransmission requires the release of many vesicle simultaneously regulated fusion of synaptic vesicles with the nerve terminals and release of neurotransmitter to synaptic cleft: docking priming fusion

SYNAPTIC POTENTIAL generated during the transmission of a nerve impulse across a synapse graded, with longer duration but lower amplitude (unlike AP which is all-or-none) magnitude related to amount of neurotransmitter released

1. Presynaptic Potential AP arriving at the terminal end of an axon2. Postsynaptic Potentiala. EPSP depolarization leads to an AP resulting from opening of ligand-gated ion channels permeability changes generating EPSP are VOLTAGE-INDEPENDENT, instead are TRANSMITTER-DEPENDENT e.g. Na+ ions flow inward generates EPSP increases postsynaptic potential depolarizationb. IPSP tends to hyperpolarize so that AP is not generated e.g. Cl- ions flow inward and/or K+ ions flow outward (membrane is simultaneously permeable to Cl- and K+ ions) generates IPSP decreases postsynaptic potential hyperpolarization

Multiple excitatory and inhibitory inputs onto dendrites and the soma SUMMATE EPSP + IPSP.

Spatial SummationTemporal Summation

several neuronssingle neuron

stimulating at the same timestimulating at different times

occurs at different sites of membraneoccurs at the same site of membrane

DENDRITES unable to transmit AP due to: few voltage-gated channels too high threshold for excitation transmit ELECTRONIC CURRENT down to the soma dendrites are long with thin membranes at least partially permeable to K+ and Cl- leaky to electric current decremental conduction (not saltatory) current spreads bc fluid (without generation of AP) dendrites summate the excitatory and inhibitory potentials

Termination of Synaptic Transmission resorption (active reuptake) of neurotransmitter or its breakdown products enzymatic degradation of neurotransmitter (e.g. Acetylcholinesterase)

Pre and Postsynaptic Inhibitions

NMJ vs. Neuron-neuron Synapse NMJ = more powerful synapses; AP in motor neuron produces AP at target muscle fiber N-N = require simultaneous inputs from presynaptic neurons to generate AP to postsynaptic neuron

Synaptic Plasticity changes in synaptic efficacy over time amplitudes of synaptic potentials are not constant over timea. Facilitation increase in amplitude of PSPs in response to successive presynaptic impulses basis of occurrence of sensitization (increased intensity of an effector response)

b. Depression decrease in amplitude of PSPs with successive presynaptic impulses basis for occurrence of habituation (decreased intensity of an effector response)

III. SENSORY RECEPTION

Receptor Cell specialized cell responsive to internal and external stimuli has the ability to convert energy into neural signal

stimulus receptor afferent nerve CNS

RECEPTOR POTENTIAL graded depolarizartion of a receptor in response to stimulation ionic basis: increased permeability of receptor membrane to all small ions, esp to Na+

Characteristics:

1. An adequate stimulus elicits a graded RP, the amplitude of which is a function of stimulus intensity

Adequate stimulus form of stimulus energy to which the receptor is most sensitive or to where it normally responds

2. The frequency of resultant AP in a receptor is a coded representation of the intensity of the adequate stimulus

Receptor potential is graded and non-propagated.Action potential is non-graded and propagated.

Sensory Transduction:absorption of stimulus energy (SE) transduction of SE to electrical signal amplification of energy integration and conduction

Sensory Reception and Processing:stimulus sense organ (accessory structure) transducer (sensory cells) action potential (nerve transmission) decoder (CNS)

TRANSDUCTION: Excitation of Receptors to Generate RP

Altered permeability of membrane to ions:1. mechanical deformation of receptors2. chemical application3. temperature change4. effects of electromagnetic radiation

Receptor Adaptation decrease in the response of a receptor to a steadily maintained stimulus over time decrease in firing of AP despite maintained depolarizationTypes:1. Tonic Receptors slowly adapting; respond for the duration of the stimulus2. Phasic Receptors radily adapting; adapts to a constant stimulus and turn offAdaptation Curves (Examples)

1. Muscle spindle receptors sensory neurons that detect change in muscle length intrafusal muscle fibers distributed among extrafusal ion channels connected by spectrin = responds to membrane deformation/stretch2. Inner hair cell transducers auditory and vestibular apparatus stereocilia and kinocilium (true for vestibular, degenerate for auditory) inner hair cells innervated by sensory + motor nerves extracellular fluid (i.e. endolymph) around hair cells = potassium-rich tip link = connects stereocilia at one end to an ion channel, one that admits potassium and calcium depolarization = movement of cilia towards kinocilium3. Olfactory receptors neurons that have ciliated terminal ends projected into the mucus of olfactory epithelium odorant receptors located in the cilia each olfactory receptor cell expresses only one type of odorant receptor = binding protein4. Gustatory receptors tongue papillae taste buds taste cell innervated by sensory nerve can be produced in different ways:a. through cationic channels (Na+, Na+/H+ cotransport)b. blocking of K+ channelsc. through secondary messengers that work close to K+ channels (bitter and sweet)d. through secondary messengers that open Cl- or non-specific ion channel5. Visual receptors rods and cones of the retina rhodopsin and cone pigments = light sensitive chemicals found in the outer segment light rhodopsin decomposition + hyperpolarization of rod receptor potential (not depolarization)

Dark StateLight Stimulation

cGMP-gated Na+ channels, which are open in the darkrhodopsin decomposition

membrane less negativecGMP-gated Na+ channels close

active transport of Na+membrane more negative

membrane more negativehyperpolarization

RMP = -40 mV normal in dark conditions

IV. MOVEMENT AND LOCOMOTION

A. SKELETAL MUSCLES

Skeletal Muscle Structure muscle cells/muscle fiber multinucleated; diameter = 10-80 m several myofibrils (1-2 m) comprise each muscle fiber sarcomere = functional unit of a myofibril

Skeletal Muscle Innervation motor unit: composed of motor neuron + all muscle cells innervated there are many motor units in a muscle a single motor neuron may innervate several fibers fewer muscle fibers per neuron the finer the movement (e.g. fingers) many muscle fibers per motor unit coarse movement (e.g. trunk muscles)

Myofibrils contain contractile elements of muscles A band (dark band) thick filaments M line center of the A band I band (light band) thin filaments Z line/disk center of I band

Sarcomere Z-M-Z Z line -actinin/titin binds actin of adjacent sarcomeres M line Mittel of sacromere

Myosin composed of two coiled polypeptide chains tails are oriented towards the center of the sarcomere (M line)

Actin composed of two coiled actin molecules + regulatory proteins TROPOMYOSIN = covers actin binding sites TROPONIN = theww binding sites (for tropomyosin, actin and Ca2+ ions)

EXCITATION

NMJ: Chemical Synapse Ach

Drugs that cause muscle spasm through Ach-like action metacholine, carbachol, nicotine destroyed very slowly by cholinesterase or not at all through Ach-ase inactivation neostigmine, physostigmine bind with Ach-ase for several hours but reversible diisopropyl fluorophosphates a nerve gas that binds with Ach-ase for weeks (lethal)

Drugs that block transmission at NMJ prevent impulse transmission curariform drugs

Myasthenia gravis autoimmune disease where antibodies attack, block or alter the Ach receptors at NMJ prevents muscle contraction mostly affect voluntary muscles muscle weakness

How is Ca2+ released from sarcoplasmic reticulum?

1. Plunger Model ryanodine receptors block Ca2+ channels AP: calcium lifts the ryanodine

2. Enzyme- or messenger-mediated mechanism

CONTRACTION

Sliding Filament Mechanism decreases in width: sarcomere, I band, H zone no change: A band, myosin and actin filaments

Cross-Bridge Cycle

Energy Sources for Contraction

Main source = ATP limited must be regenerated through: Direct Phosphorylation creatine phosphate/phosphocreatine (CP) high energy molecule found in muscle fibers creatine phosphokinase transfers PO4 from CP to ADP

RELAXATION

Contraction-Relaxation Steps Requiring ATP splitting of ATP by myosin ATPase provides energy for power stroke of cross bridge binding of fresh molecule of ATP to myosin leads to cross bridge detachment from actin filament at end of power stroke so cycle can be repeated active transport of Ca2+ back to sarcoplasmic reticulum during relaxation calsequestrin (in sarcoplasmic reticulum)

Isotonic ContractionsIsometric Contractions

muscle shortens with constant tensionmuscle remains same length during contraction; tension is variable

load < tensionload > tension

Slow Muscle FibersFast Muscle Fibers

slow but prolonged responserapid contraction but short response

slow contraction, longer durationextensive SR for rapid release of Ca2+

associated with smaller fibers innervated by smaller nervesassociated with large fibers which elicit great strength of contraction

extensive blood supply and mitochondrialess extensive blood supply and mitochondria

high myoglobin red/dark muscleslow myoglobin white muscles

low levels of myosin ATPase and glycolytic enzymeshigh levels of myosin ATPase and glycolytic enzymes

Type I/Slow Oxidative = depends on aerobic processesType IIA/Fast Oxidative Glycolytic (FOG) = intermediate

Type IIB/Fast Glycolytic = anaerobic processes

B. SMOOTH MUSCLES

Smooth Muscle Structure

no striations no sarcomere no troponin no T-tubules less developed SR

Smooth Muscle Innervation: Autonomic no NMJ neurotransmitters are released from varicosites

Types:1. Multi-unit one nerve per muscle cell neurogenic e.g. muscles found in iris of eyes, trachea, arteries2. Single-unit one nerve + gap junctions myogenic e.g. peristaltic wave in GI tract

Smooth Muscle Contraction

1. With excitation-contraction coupling through neural input (autonomic nervous system) Parasympathetic: Ach as NT binding with muscarinic receptor Sympathetic: NE as NT2. Without E-C coupling through hormones, paracrine agents (effects/signals neighboring cells), etc. involving secondary messengers

C. CARDIAC MUSCLES

Cardiac Muscle Structure

with striation with troponin with developed SR with T-tubules

INTERCALATED DISCS + gap junctions (unique feature) regions of low electrical resistance for action potential transmission marks adjacent muscle cells innervated by autonomic nervous system myogenic ECF + SR = calcium sources Ach is inhibitory to contraction (vs. skeletal = induces contraction) NE is excitatory (responsible for fast heart rate)

Action Potential in Cardiac Myocyte

Dyhydropyrinidine receptors are unable to affect function of ryanodine receptors,

instead, the release of large amounts of Ca2+ opens RyRs.

SmoothCardiac

excitation: requires both extra and intracellular sources of Ca2+

contraction: Ca2+ binds with calmodulin (vs. skeletal = troponin)contracts more slowly and exhibit more prolonged contraction with less ATPcontraction: mechanism is similar to skeletal but more calcium is released for AP generation more actin-myosin interaction = to avoid tetany of heart

relaxation: requires myosin phosphatase enzyme to dephosphorylate myosinrelaxation:1. active transport of Ca2+ back into SR during relaxation2. 3 Na : 1 Ca antiport in SR and sarcolemmal pump

sources of Ca2+ are both extracellular and intracellular (SR)

extracellular Ca2+ allows prolonged contraction

intracellular increase in Ca2+ = due to nerve stimulation or hormonal/local factors

Thick Filament Regulation (Phosphorylation of Myosin):

calmodulin + Ca2+ activates myosin light-chain kinase (MLK) adds phosphate to myosin phosphorylated myosin binds to actin contraction

[vs. skeletal = Thin Filament Regulation] depends on the uncovering of the thin filament (actin)

D. NON-MUSCLE CELLS

Cytoskeleton network of protein filaments in eukaryotic cell cytoplasm that provides shape, support and movement cytomuslculature

Three types of protein filaments:1. Actin Filaments (Microfilaments) maintain cell shape by resisting tension (pull) move cells via muscle contraction or cell crawling divide animal cell into two move organelles and cytoplasm in plants, fungi and animals2. Intermediate Filaments maintain cell shape by resisting tension (pull) anchor nucleus and some other organelles3. Microtubules maintain cell shape by resisting compression (push) move cells via flagella or cilia move chromosomes during cell division move organelles provide tracks for intracellular transport

Actin Filaments in Crawling Cells (Amoeboid)

1. Trailing edge where most actin is heavily distributed2. Leading edge pulls the cell forward3. Stress fibers lie on ventral surfaces of cells made up of actin-myosin form in response to tension generation within cell; adhesion and deadhesion of cell to substratum

Contractile bundle stress fibers Cell cortex gel beneath the PM actin-myosin support + stiffens the fluid-like (gel) membrane randomly arranged Filopodium thinner projections of cells actins are tightly arranged in parallel bundleGrowth cone developing axon (terminal portion) not yet synaptically connected guides the axon in looking for synaptic target lamellipodium + filopodium + microfilaments

Addition of G-actin to F-actin filopodium

Cells with amoeboid movement of amoebas embryonic cells during development invasion of tissues by leukocytes (macrophages) migration of cells during wound-healing metastasis of cancer cells

Actin-binding Proteins: -actin, Filamin, Fimbrin determine the form + function of actin filaments -actin = contractile bundles filamin = gel fimbrin = parallel bundles

Steps in Cell Crawling

1. Protrusion of the leading edge polymerization of actin subunits to form actin fils2. Adhesion to certain substrates mostly stress fibers contribute to adhesion cortex, hindi humahaba pero nagmo-move *Deadhesion trailing end3. Traction interaction of actin-myosin

Cytoplasmic Gel-Sol Conversion: Role in Locomotion

Gel-Sol actin cytoskeleton transitioning between solid-like elastic material (gel/gelation) and a solution-like viscous material (sol/solation) from gel to sol; gel at rest, sol for contraction induced by presence of calcium

CILIA occur in groups; shorter power stroke: counters a force; cilium bends at the base recovery stroke: bend propagates up the cilium (bottom to top high energy) motion with single bend

FLAGELLA single; longer wave-like motion = reverse bend-forward bend recovery stroke: bend propagates up the flagellum motion with several bends

Where cilia is found/used: respi tract to remove mucus uterus for propulsion of egg cell attachment is called basal body beat metachronically smoke (cigarette) loosens cilia lining in lungs

Axoneme in Cilia and Flagella similarly organized 9+2 arrangement of microtubules -tubules = 13 profilaments -tubules = 11 profilaments central = 13 profilaments basal body = no central fils 9+0 radial spokes = linkages of outer doublets to central nexins = links adjacent doublets dyein arms inner and outer protein motor molecules that walk along adjacent microtubules ATPase activity: hydrolysis of ATP associated with reattachment of the dyein arms to the adjacent -tubule but at a different location a sliding motion of adjacent outer tubule structures binding of ATP release of the dyein arms from the adjacent -tubule sliding microtubule

In a cilium/flagellum, two adjacent doublets cannot slide far because they are physically restrained by proteins so they bend.

(A) Trypsin-treated axoneme of sperm tail nexin linkers and radial spokes cleaved ATP addition sliding of microtubules axoneme is 7-8 times longer(B) ATP-dependent movement of outer doublets restricted by cross-linkage proteins in order for sliding to be converted into bending of axoneme