Flashcards in Medical Physiology Block 1 Week 3 Deck (68):
Distinguish ionic vs. capacitative currents through a cell membrane. Relate each to the underlying ion movements.
When we suddenly change voltage to a new value, a transient capacitative current flows as charge flows onto the capacitor. The capacitative current is maximal at the beginning of the square pulse, when charge flows most rapidly onto the capacitor, and then falls off exponentially with a time constant of RC. When we suddenly decrease the voltage to its original value, I C flows in the direction opposite that observed at the beginning of the pulse. Thus, I C appears as brief spikes at the beginning and end of the voltage pulse.
In response to a subthreshold injection of current into an axon, describe the time course of the resulting voltage change. Discuss when the current is capacitative vs. ionic.
When we inject a square pulse of current across the membrane, the voltage changes to a new value with a rounded time course determined by the RC value of the membrane. (Early current: capicitative; late current: ionic)
List the factors that determine the speed of a subthreshold depolarization produced by an injection of current. (Why is there a delay in propagation of an action potential down in axon?)
length constant (resistance of the cytoplasm and properties of leaky ionic current at rest)
Explain why there is a tradeoff between stimulus intensity and duration to reach threshold for generation of an action potential, for short but not long stimuli.
It is the product of strength and duration that determines excitability (charge = current x time); regardless of the stimulus duration, successful stimulation requires a minimum strength
Explain how small, subthreshold voltage changes decay with distance along an axon
The electrotonic potential decays as a function of distance from stimulus
Define a current loop
The cytosol of the active region, where the membrane is depolarized, has a slight excess of positive charge compared with the adjacent inactive regions of the cytosol, which have a slight excess of negative charge. This charge imbalance within the cytosol causes currents of ions to flow from the electrically excited region to adjacent regions of the cytoplasm. Because current always flows in a complete circuit along pathways of least resistance, the current spreads longitudinally from positive to negative regions along the cytoplasm, moves outward across membrane conductance pathways (“leak channels”), and flows along the extracellular medium back to the site of origin, thereby closing the current loop. Because of this flow of current (i.e., positive charge), the region of membrane immediately adjacent to the active region becomes more depolarized, and V m eventually reaches threshold.
Define length constant, and explain the effect of axon diameter on the length constant.
length constant (resistance of the cytoplasm and properties of leaky ionic current at rest); As axon diameter increases, the conduction velocity of action potentials increases because the internal resistance of the axoplasm is inversely related to the internal cross-sectional area of the axon.
Define myelination, and explain how it speeds propagation of an action potential. Know the location of Na+ channels in a myelinated axon
In a myelinated axon, the ionic current flows only through the nodes, where there is no myelin and the density of Na + channels is very high. Ionic current does not flow through the internodal membrane because of the high resistance of myelin. As a result, the current flowing down the axon is conserved, and the current density at the nodes is very high. This high current density results in the generation of an action potential at the node. Thus, the regenerative action potential propagates in a “saltatory” manner by jumping from node to node. Note that the action potential is actually conducted through the internodal region by capacitative current due to charge displacement across the membrane arising from the resistance-capacitance properties of the membrane
Discuss some of the major differences in electrical activity in different cell types.
Some action potentials are brief; others are repetitive (cardiac and smooth muscle); The shape of the action potential is subject to hormonal modulation in certain cell types.Modulation of the shape and frequency of action potentials occurs by various biochemical regulatory mechanisms that affect the function of ion channels; the resting potential varies; the action potential peak varies; and the action potential duration varies
List several major classes of voltage-dependent ion channels
K; calcium and voltage gated potassium channels; Na and Ca channels; hyperpolarization activated cyclic nucleotide gated channel
Draw the transmembrane structure of typical Kv-type K+ channels. How are sodium channels different?
The S1-S4 domain containing the voltage-sensing S4 (every third amino acid is positively charge) element is spatially separated from the K + pore domain (S5-P-S6); The central square portion of the Kv1.2 pinwheel is the pore—formed by the assembly of four S5-P-S6 domains, one from each monomer; On depolarization, the S4 segment presumably moves within the membrane toward the extracellular side of the membrane. This mechanical movement of the S4 segment shifts an α-helical S4-S5 linker, causing a bending of the S6 transmembrane α helix from a linear configuration in the closed state to a curved configuration in the open state of the channel shown. Thus, voltage-dependent channel activation is an electromechanical coupling mechanism; 4 domains with linker regions (different type of B domain (transmembrane)
State the region most responsible for sensing voltage in (e. g.) Kv channels. State the region most responsible for selectivity among ions.
S4 segment (S1-S4); S6 (The PVP sequence (Pro-Val-Pro) on S6 is critical for gating)
List several mechanisms that can modulate the activity of voltage-dependent ion channels.
Expression (different isoforms); accessory subunits (some act as blocks for inactivation); signaling (G-coupled receptors); interaction with membrane lipids (PIP2))
Blocking potassium conductance (permeability) by TEA does what to an action potential?
Reduces the strength and duration of the hyperpolarization state of the AP; if this occurs at the synaptic terminal, more calcium channels would be opened
Drug X, when applied to a nerve axon, results in both a gradual decrease in the amplitude of the individual action potential and a slow (several hours) repolarization of the resting membrane potential. The drug is most likely blocking what?
When extracellular sodium decreases, the peak of the action potential ___?
If [Ca 2+]o is progressively increased above the normal physiological level, the voltage activation range of Na + channels progressively does what?
progressively shifts to a higher voltage range (less excitability and can possible lead to muscle weakness)
How are L-type calcium channels different from other calcium channels?
When they open, they tend to stay open (other calcium channels inactivate quicker) (found on skeletal muscle, cardiac muscle, and some smooth muscle)
Describe an outwardly rectifying potassium channel.
delayed conductance; inactivation gradually speeds up from Kv1.1 to Kv1.4; mechanisms of inactivation: n terminal domain or beta subunit (ball and chain)
What is peculiar about calcium activated potassium channels?
Both potassium and voltage can activate the channel (may be synergistic)
Describe inward rectifying potassium channels.
turn off upon depolarization (Magnesium block; pass outward current at physiological voltages)
Describe the physical structure of an electrical synapse. What advantage, disadvantage does an electrical synapse have with respect to a chemical synapse.
mediated by gap junctions (gating and voltage dependence determined by connexins (6)); separated by less than 3 nm; immediate action; disadvantage: only allows small ions to pass between cells
List, in chronological order, the active ionic conductances in the presynaptic terminal that are responsible for the initiation and cessation of chemical synaptic transmitter release.
sodium, potassium, and calcium
Define the fundamental mechanisms that define an ionotropic synaptic receptor and a metabotropic synaptic receptor. Contrast the kinetic and biochemical characteristics of these two different receptor classes.
ionotropic: uses ion channels (fast); metabotropic : second messengers (may take seconds to minutes)
Define the anatomical term and functional characteristics of a “motor unit”
The axon of a motor neuron typically branches near its termination to innervate a few or many individual muscle cells. The group of muscle fibers innervated by all of the collateral branches of a single motor neuron is referred to as a motor unit
List and define the function of specialized proteins in the plasma membrane of the “endplate"
An individual end plate consists of a small tree-like patch of unmyelinated nerve processes that are referred to as terminal arborizations. The bulb-shaped endings that finally contact the muscle fiber are called boutons (active zones); The postsynaptic membrane of the skeletal muscle fiber lying directly under the nerve terminal is characterized by extensive invaginations known as postjunctional folds. These membrane infoldings greatly increase the surface area of the muscle plasma membrane in the postsynaptic region; A particular region of the muscle basement membrane (synaptic cleft) called the synaptic basal lamina contains various proteins (e.g., collagen, laminin, agrin) that mediate adhesion of the neuromuscular junction (also contains AchE)
Define the term “miniature endplate potential” and understand the physical basis for quantal synaptic transmission.
The contents of one synaptic vesicle (one quantum) produce a miniature end plate
potential (does not need a calcium channel to be open)
Define the physiological role of acetycholinesterase. Describe how manipulation of acetylcholinesterase is used as a therapy for a pathological state.
ACh is degraded to acetyl CoA and choline by acetylcholinesterase (AChE) on the muscle end plate.
One-half of the choline is taken back into the presynaptic ending by Na+–choline
cotransport and used to synthesize new ACh (blocked by Neostigmine, physostigmine, and DFP)
List the main proteins thought to control vesicular neurotransmitter exocytosis: synaptotagmin, synaptobrevin, syntaxin and snap-25. Understand how they interact to facilitate vesicle fusion and how they are re-set following fusion.
Rab3 acts as a switch; Three SNARE proteins form a complex (syntaxin & SNAP-25 on the nerve terminal membrane; synaptobrevin, vesicle membrane); Binding of calcium to to synaptotagmin triggers fusion and release of the neurotransmitter into the cleft; NSF ATPase and alpha-SNAP hydrolyze the SNARE complex
Describe synthesis and storage of ACh in the presynaptic terminal
Choline acetyltransferase catalyzes the formation of ACh from acetyl coenzyme A (CoA) and choline in the presynaptic terminal. The ACh moves into the synaptic vesicle through a specific ACh-H exchanger, which couples the inward transport of ACh to the efflux of H +. Energetically, this process is driven by the vesicular proton electrochemical gradient (positive voltage and low pH inside), which in turn is produced by a vacuolar-type H + pump fueled by ATP
What is the structure of a nicotinic acetylcholine receptor
The nicotinic AChR is a heteropentamer with the subunit composition of α 2βγδ. These subunits are homologous to one another, and each has four membrane-spanning segments (M1 to M4). (2 acetylcholine can bind near alpha subunits)
How do fetal Ach receptors differ from adult Ach receptors?
single channel conductance, mean open time, membrane distribution (fetal are non-junctional), and subunit composition
What is the effect of lidocaine on a Ach receptor?
Block the pore intermittently (channel flickering)
Difference between potentiation and facilitation?
Potentiation is long term
How are synaptic vesicles and mitochondria transported to the active site?
By fast axonal transport (microtubules); peptide based neurotransmitters are packaged in the Golgi
What is the effect of Botulism?
Blocks various SNARE proteins
Increasing extracellular magnesium concentration will alter all what components of chemical synaptic transmission?
presynaptic calcium influx, presynaptic Ach release, endplate potential, and postsynaptic sodium influx (not MEPP)
What does ω-Conotoxin do?
Blocks calcium channels
Describe how an action potential in a motor neuron produces an action potential in skeletal muscle at the neuromuscular junction
Action potential propagates in two directions following depolarization at the nerve END PLATE; 2. the conformational changes in the four L-type Ca 2+ channels induce a conformational change in each of the four subunits of another channel—the Ca 2+-release channel (ryanodine)—that is located in the SR membrane (mechanical coupling of the L-type channels and ryanodine receptor (tetramer)) (depolarization induced calcium release (DICR) accounts for 50% of calcium release from sarcoplasmic reticulum; Half of the ryanodine receptors are not bound by DHP receptors and respond to increased sarcoplasmic calcium concentrations by increasing the conductance of calcium from their own channel (calcium induced calcium release (CICR) account for 50% of calcium release from sarcoplasmic reticulum)
Describe the myofibril and identify the major bands and lines of the sarcomere
Repeating units of sarcomeres account for the unique banding pattern in striated muscle. A sarcomere runs from Z line to Z line. I band (actin); A band (myosin); h band (myosin-actin); m line = middle
Identify and describe the function of the proteins associated with the sarcomere of skeletal muscle.
Titin responsible for the elasticity of the muscle (extends from the M band to the Z line); Nebulin is thought to determine the length of actin thin filaments; Dystrophin attaches the sarcomere unit to the sarcolemma; Alpha actinin is associated with the Z line and anchors the thin filament
Describe thin filaments
Individual tropomyosin molecules consist of two identical α helices that coil around each other and sit near the two grooves that are formed by the two helical actin strands (attached to 7 actin mononers) (movement of one troponin complex unmasks 7 myosin binding sites; for every tropomyosin, there is one troponin complex); troponin complex: C bind calcium, I binds actin; T binds tropomyosin
Describe thick filaments
Components of myosin: alkali light chain, regulatory light chain, and heavy chains; Heavy chains consist of a rod, hinge, and head region (The heads of the heavy chains—also called S1 fragments—each possess a site for binding actin as well as a site for binding and hydrolyzing ATP)
Describe the time course of the change in the concentration of intracellular calcium associated with a single muscle contraction.
There is a substantial delay between peak in calcium current and a twitch
Describe the cross bridge
First, myosin is bound to actin; ATP binding to S1 breaks the myosin-actin complex; hydrolysis of ATP causes a change in conformation of S1 and results in binding of myosin to actin; the power stroke is the result of the phosphate leaving the S1 region; ADP is lost after the power stroke.
How is contraction stopped?
Relaxation occurs when Ca2+ is reaccumulated by the SR Ca2+-ATPase (SERCA). Intracellular Ca2+ concentration decreases, Ca2+ is released from troponin C, and tropomyosin again blocks the myosin-binding site on actin; calcium can also leave the cell through NCX or calcium pump on sarcolemma; c. If the sarcoplasmic reticulum STIM1 membrane protein detect low calcium concentrations in the sarcoplasmic reticulum, it will move itself nearby the sarcolemma and associates with a calcium channel known as ORAI1
T/F: During each cross-bridge cycle, calcium binds and then dissociates from TnC only to bind again to initiate the next cycle
Which molecule sequesters calcium in the sarcoplasmic reticulum?
What is true of an isometric contraction of skeletal muscle?
The length of the muscle stays constant during the contraction (think pulling against an immovable object; with gravity); the magnitude of the contraction depends on muscle length (if stretched, the myosin-actin complex will not be as efficient; if pulled closer together, the myosin-actin complex is not as efficient in generating tension)
What is true of an isotonic contraction of skeletal muscle?
Maximum velocity of shortening (Vmax) occurs when the load on the muscle = 0; Vmax = 0 when the load on the muscle is > Fmax
What is passive tension? What causes it?
tension measured before muscle contraction (result of the elasticity of Titin; increases as a muscle is stretched)
What are satellite cells?
Mononucleated, muscle stem cells that prevent muscles from dying following damage
The maximum rise in intracellular calcium in response to a twitch stimulation is what percentage of the rise in intracellular calcium during a fused tetanic contraction?
The speed of contraction of muscle types from fastest to slowest is:
IIB - IIA - I
Which muscle fibers are referred to a white muscle fibers?
Which muscle fibers depend primarily on glycolysis for ATP production?
Which muscle fibers are the most fatigue resistance?
Type I (oxidative ATP production)
The maximum velocity of shortening is greatest for which fiber type? The maximum force/cross sectional area is greatest for which fiber type?
Strength training will cause what? endurance training?
muscle hypertrophy and increase the glycolytic enzymes; grow new microvessels and increase mitochondria
T/F: The percentage of fast and slow muscle fibers within a whole muscle is fixed and cannot change due to exercise.
What are characteristics of contraction of cardiac muscle?
synctium (gap junctions and desmosomes); contain phospholamban (regulator of SERCA); different SERCA and ryanodine receptor than skeletal muscle; only calcium induced calcium release
What are characteristics of smooth muscles?
Multi unit v single unit; contain actin, myosin, alpha actinin, dense bodies and tropomyosin; filament must be built upon stimulation; ECC can be CICR, IP3 activated, or activated by other G-protein receptors
To what intracellular protein does calcium bind to activate contraction in smooth muscle?
calmodulin binds to 4 calcium (phosphorylates myosin regulatory light chain through MLCK)
What causes smooth muscles to relax after contraction?
dephosphorylation of the myosin light chain
Which of the following steps are slowed to produce a latch state in smooth muscle?
ADP release from the myosin head
Why can a cardiac cell never tetanize?
Duration of the action potential
Is a larger length constant mean faster conduction of an action potential along a nerve fiber?
Yes; membrane resistance = numerator; axoplasm resistance = denominator