1
Q
Where is cardiac muscle found and is it voluntary or involuntary?
A
Location: Found only in the heart. Control: Innervated by the autonomic nervous system (involuntary/no conscious control). Excitability: It is self-excitatory because of the pacemaker function of autorhythmic cells.
2
Q
How does cardiac muscle structure differ from skeletal muscle?
A
Similarities: Like skeletal muscle, it is striated and organized into sarcomeres. Differences: Fibers are shorter than skeletal muscle. Usually contain only one nucleus. Fibers are extensively branched.
3
Q
What are intercalated discs and what two structures do they contain?
A
Definition: Structures that connect cardiac muscle fibers to one another at their ends. Location: They are part of the sarcolemma. Components: They contain two key structures: gap junctions and desmosomes.
4
Q
What is the function of gap junctions in cardiac muscle and what is a “syncytium”?
A
Function: Form channels between adjacent fibers that allow the quick transmission of action potentials. Result: Ensures coordinated contraction of the entire heart. Syncytium: The heart acts as a single functional unit, called a syncytium.
5
Q
What is the specific function of desmosomes in cardiac muscle?
A
Definition: A cell structure that anchors the ends of cardiac muscle fibers together. Purpose: Ensures the cells do not pull apart during the stress of individual fibers contracting.
6
Q
What is the main functional benefit of the branching pattern and intercalated discs?
A
Together, these features ensure faster signal propagation and contraction in three dimensions.
7
Q
How does the basic filament organization of cardiac muscle compare to skeletal muscle?
A
The basic organization is comparable. It has repeating I bands and A bands. The region between two adjacent Z lines is the sarcomere (the contractile unit).
8
Q
What proteins make up the thin filaments in cardiac muscle?
A
Actin, tropomyosin, and troponin. (This is the same as in skeletal muscle).
9
Q
What three other key proteins are associated with the thin filaments and what do they do?
A
Nebulin: Extends along the actin filament and may set its length during assembly. alpha-actinin: Anchors the actin filament to the Z line. Tropomodulin: Resides at the end of the actin filament and regulates its length.
10
Q
What proteins make up the thick filaments and how are they anchored?
A
Composition: Composed of myosin and extend from the center of the sarcomere. Anchor: They are tethered to the Z lines by a large, elastic protein called Titin.
11
Q
How do the T-tubules of cardiac muscle compare to skeletal muscle?
A
The sarcolemma contains invaginations (T-tubules) that are comparable to those in skeletal muscle. Note: Slide 4 shows they are less extensive than in skeletal muscle.
12
Q
How does the Sarcoplasmic Reticulum (SR) of cardiac muscle compare to skeletal muscle
A
The SR surrounds the myofibrils, similar to skeletal muscle. Key Difference: The SR in the heart is less dense and not as well developed.
13
Q
What is the “diad” in cardiac muscle?
A
The structural pairing of the Sarcoplasmic Reticulum (SR) and a T-tubule is referred to as a “diad”. (This is different from the “triad” in skeletal muscle).
14
Q
What are the two major types of cardiac muscle cells and their percentages?
A
Conducting cells (constitute 1% of the cells). Contractile cells (constitute 99% of the cells in the atria and ventricles).
15
Q
What is the primary function of conducting cells?
A
They form the conduction system of the heart. They function similarly to neurons, initiating and propagating the action potential that travels throughout the heart and triggers contractions that propel the blood.
16
Q
What specific group of cells initiates the heartbeat, and where are they located?
A
Pacemaker cells (a type of specialized conducting cell). They are located in the Sinoatrial (SA) node. They initiate rhythmic impulses and regulate the heart rate.
17
Q
Conducting cells consists of what?
A
Nodes and internodal pathways
18
Q
What is the primary function of contractile cells?
A
They are activated by impulses from neighboring cells. They conduct impulses and produce contractions. They generate the force that pumps blood through the body.
19
Q
What is the key anatomical difference between pacemaker cells and contractile cells?
A
Pacemaker (conducting) cells are anatomically distinct because they have no organized sarcomeres. Consequence: They do not contribute to the contractile force of the heart.
20
Q
What are the main components of the conduction system shown on the diagram (Slide 5)?
A
SA node (Sinoatrial) AV node (Atrioventricular) AV bundle Internodal pathways Bundle branches (Left and Right) Purkinje fibers
21
Q
What is “autorhythmicity” in cardiac conductive (pacemaker) cells?
A
It is the ability to be self-excitable and depolarize to threshold to fire action potentials on their own. This is happens in intervals and is what sets the rate of the heartbeat.
22
Q
Why don’t conductive cells have a stable resting potential?
A
Because they have sodium ‘leak’ channels that cause an unstable resting potential (spontaneous depolarization). These channels are also known as HCN channels (hyperpolarization-activated cyclic nucleotide-gated channels) funny channels.
23
Q
What is the “prepotential” (or “spontaneous depolarization”) and what causes it?
A
It is the slow rise in membrane potential from -60 mV up to about -40 mV (threshold). It is caused by a slow influx of sodium (Na⁺) through the ‘leak’ (HCN/funny) channels, which are hyperpolarization-activated.
24
Q
What happens when the pacemaker cell’s prepotential reaches the threshold (approx. -40 mV)?
A
The Na⁺ ‘leak’ (funny) channels start to close. L-type calcium ion channels (DHPRs) open. Ca²⁺ enters the cell, causing a rapid depolarization (the action potential) up to approximately +15 mV.
25
How does the pacemaker cell repolarize after the action potential (at +15 mV)?
The calcium ion channels (DHPRs) close. K⁺ channels open. This allows a rapid outflux of K⁺, which results in repolarization (the potential falls).
26
How does the pacemaker cycle repeat once repolarization reaches its minimum (approx. -60 mV)?
The K⁺ channels close. The Na⁺ 'leak' channels (HCN/funny) open (because they are activated by hyperpolarization). This starts the prepotential phase (slow Na⁺ influx) all over again.
27
What is the overall function of pacemaker cells?
Although they are specialized muscle cells, their function is to initiate and propagate the action potential that travels throughout the heart muscle. This action potential triggers the contractions that propel the blood.
28
Do cardiac contractile cells initiate their own action potential?
No. Contractile cells normally do not initiate their own action potential, but rather wait for an impulse to reach them (e.g., from a conducting cell).
29
What happens during the rapid depolarization phase of a contractile cell AP?
Stimulated by an action potential, voltage-gated Na⁺ channels rapidly open. This causes a rapid influx of Na⁺, raising the membrane potential from -90mV to +30 mV. At +30mV, the Na⁺ channels close. This phase lasts 3-5 ms.
30
What ionic events cause the "plateau" phase and how long does it last?
he membrane potential declines relatively slowly. This is caused by the opening of slow Ca²⁺ channels (allowing Ca²⁺ in) while a few K⁺ channels are open (allowing K⁺ out). This phase lasts approximately 175 ms.
31
What ionic events cause the repolarization phase in a contractile cell?
Once the potential reaches approximately zero (0) mV, the slow Ca²⁺ channels close. More K⁺ channels open, allowing K⁺ to exit the cell. The membrane potential drops until it reaches resting levels. This phase lasts approximately 75 ms.
32
What is the total approximate duration of a contractile cell action potential?
The entire event lasts between 250 and 300 ms. So very long
33
What is the main functional purpose of the long plateau and long action potential?
The sustained depolarization plateau (caused by Ca²⁺ entry) accounts for the long refractory periods. This is required for the cardiac muscle cells to pump blood effectively (i.e., contract and relax) before they are capable of firing for a second time.
34
Compared with conducting cells and skeletal muscles, contractile cells have what?
relatively long action potentials and a sustained depolarization plateau. The plateau is produced by Ca2+ entry though VGCC in the sarcolemma of cardiac muscle fibers.
35
How does the source of Ca²⁺ for contraction differ in cardiac muscle compared to skeletal muscle?
Unlike skeletal muscle (which gets Ca²⁺ only from the SR), a large percentage of the Ca²⁺ that initiates contraction in cardiac muscle comes from outside the cell (i.e., from the ECF, entering during the plateau phase).
36
What is the initial event of E-C coupling in cardiac contractile cells?
Action potentials (AP) generated by pacemaker cells traverse to the contractile cells, where the AP invades the T-tubule. Depolarization at the T-tubule activates the L-type calcium channels (DHPRs).
37
What is the key difference in E-C coupling between skeletal muscle and cardiac muscle?
Skeletal: Uses "Electromechanical coupling". The DHPR is directly coupled (physically interacts) with the RyR. Cardiac: Uses "Electrochemical coupling". The DHPR is not directly coupled to the RyR.
38
What is the specific mechanism of Ca²⁺ release in cardiac muscle, and what is it called?
Activation of DHPRs causes an influx of Ca²⁺ across the plasma membrane (from outside the cell). This influx of Ca²⁺ then triggers the RyRs on the SR to open and release more Ca²⁺. This mechanism is called Ca²⁺-induced Ca²⁺ release (CICR).
39
What evidence supports that the DHPR isoform is the basis for this difference?
If you express the cardiac DHPR isoform in skeletal muscle cells, those modified skeletal cells now require extracellular Ca²⁺ for contraction.
40
In cardiac muscle, what are the two sources that contribute to the rise in intracellular Ca²⁺?
The DHPRs (allowing Ca²⁺ influx from outside the cell). The RyRs (releasing Ca²⁺ from the SR via CICR).
41
How is contraction itself controlled at the molecular level in cardiac muscle?
Just like in skeletal muscle, cardiac muscle contraction is controlled by troponin. The molecular mechanism is also the repeated cross-bridge formation and dissociation (cross-bridge cycle).
42
How does cardiac muscle relaxation (ending contraction) occur?
Contraction ends when Ca²⁺ is re-absorbed by the SR via the SERCA pump. Ca2+ in the SR can be buffered by calsequestrin, a protein in the lumen of the SR.
43
What is the "Contraction-promoting pathway"
Adrenaline/Noradrenaline binds to a $\beta$-Adrenergic receptor. This activates PKA, which phosphorylates the L-type Ca²⁺ channel (DHPR), promoting more Ca²⁺ influx and stronger contraction.
44
What is the "Relaxation-promoting pathway"
PKA also phosphorylates Phospholamban (-P). Phosphorylated Phospholamban stops inhibiting SERCA, allowing SERCA to work faster. This speeds up Ca²⁺ re-uptake into the SR, promoting faster relaxation.
45
What is the definition of "Calcium-Induced Calcium Release" (CICR)?
It is a biological process whereby Ca²⁺ induces Ca²⁺ release from intracellular Ca²⁺ stores (e.g., the ER/SR).
46
What is the underlying mechanism of CICR?
A rise in cytosolic Ca²⁺ increase activates RyRs (Ryanodine Receptors), which are Ca²⁺ sensitive. This activation causes further Ca²⁺ release from the ER/SR stores.
47
How does Ca²⁺ affect RyRs vs. IP3Rs?
Ca²⁺ can directly activate RyRs. Ca²⁺ sensitizes IP3Rs to IP3Rs (making them more likely to open).
48
What are three potential initiation events that can trigger CICR?
External Ca²⁺ influx through channels on the plasma membrane (PM). GPCR activation to IP3Rs to IP3Rs Ca²⁺ release (this initial release then triggers CICR from RyRs). Ca²⁺ release from lysosomes, which then activates neighboring RyRs.
49
How important is CICR in skeletal muscle vs. cardiac muscle?
Skeletal Muscle: Although first discovered there, it is unlikely to be the primary mechanism for SR Ca²⁺ release (which is electromechanical). Cardiac Muscle: CICR is thought to be CRUCIAL for excitation-contraction coupling.
50
Is CICR only found in muscle cells
No. It is a widely occurring cellular signaling process present in many non-muscle cells. Example: Insulin-secreting pancreatic beta cells.
51
What is a "Calcium Spark" and how is it produced?
Definition: It is a local cytosolic Ca²⁺ transient that can be visualized as a spark. Mechanism: It results from Ca²⁺-induced Ca²⁺ release from several RyRs in a RyR cluster (concerted openings).
52
In which cell types are Ca²⁺ sparks observed?
Muscles (skeletal and cardiac). Smooth muscles. Neuroendocrine cells (e.g., chromaffin cells). Neurons.
53
What is the duration of a Ca²⁺ spark (Normal vs. Long-lasting)?
Normal: Brief duration in the range of 10 to 100 ms. Long-lasting: Can last several hundred milliseconds.
54
What local calcium concentration does a Ca²⁺ spark deliver?
A spark can deliver ~100 - 300 nM (nanomolar) local calcium levels. Levels can even reach μM (micromolar) concentrations.
55
How is cardiac muscle contraction regulated (i.e., thick-filament or thin-filament)?
Contraction of cardiac muscle is thin-filament regulated (just like skeletal muscle). An elevation in intracellular Ca²⁺ is necessary to promote actin-myosin interaction.
56
What is the state of the thin filament at low intracellular Ca²⁺ (e.g., < 50 nM)?
At low intracellular Ca²⁺, the binding of myosin to actin is blocked by tropomyosin.
57
What is the first step of thin-filament activation when cytosolic Ca²⁺ increases?
Ca²⁺ (released during the action potential) binds to troponin C.
58
What happens after Ca²⁺ binds to troponin C?
This binding results in a conformational change in the troponin/tropomyosin complex. This causes tropomyosin to slip into the groove of the actin filament.
59
What is the final result of the conformational change caused by Ca²⁺ binding?
The myosin binding sites on the actin filament are exposed.
60
What conditions are required for the cross-bridge cycle to continue contracting the muscle?
Cytosolic Ca²⁺ must remain elevated. The myosin binding sites must remain exposed.
61
How does the four-step cross-bridge cycle in cardiac muscle compare to skeletal muscle?
The cross-bridge cycle in cardiac muscle is a four-step cycle that is identical to that described for skeletal muscle.
62
How does skeletal muscle relaxation occur?
It simply requires the re-accumulation of Ca²⁺ by the SR through the action of the SERCA pump (a Ca²⁺ pump in the SR membrane).
63
Why is cardiac muscle relaxation more complex than skeletal muscle relaxation?
Because some "trigger Ca²⁺" enters the cardiac muscle cell from the outside through DHPRs during each action potential. A mechanism must exist to extrude this trigger Ca²⁺ from the cell.
64
What would happen if this "trigger Ca²⁺" was not extruded from the cardiac cell?
The amount of Ca²⁺ in the cell/SR would continuously increase. This would result in Ca²⁺ overload and lead to cell damage.
65
What are the two main Ca²⁺ extrusion mechanisms on the sarcolemma (cell membrane) that remove Ca²⁺ from the cell?
The sarcolemmal 3Na⁺-Ca²⁺ antiporter (also called NCX). The sarcolemmal Ca²⁺ pump (a Ca²⁺-ATPase).
66
Why is it difficult to extrude Ca²⁺ from the cell?
It must be accomplished against a large chemical gradient. Extracellular [Ca²⁺] is in the millimolar (mM) range. Intracellular [Ca²⁺] is in the submicromolar (nM/μM) range.
67
How does the sarcolemmal Ca²⁺ pump (extrusion mechanism 1) work?
It uses the energy from ATP hydrolysis to extrude Ca²⁺ from the cell (against its gradient).
68
How does the 3Na⁺-Ca²⁺ antiporter (extrusion mechanism 2) work?
It uses the Na⁺ gradient (which is much higher outside the cell) to power the "uphill" movement of Ca²⁺ out of the cell.
69
What three mechanisms all contribute to the relaxation of cardiac muscle by decreasing cytosolic Ca²⁺?
The SERCA pump (pumps Ca²⁺ into the SR). The sarcolemmal 3Na⁺-Ca²⁺ antiporter (pumps Ca²⁺ out of the cell). The sarcolemmal Ca²⁺ pump (pumps Ca²⁺ out of the cell).
70
What are the two different types of cells in the heart and their basic functions?
1. Conducting cells (or pacemaker cells): Generate and carry the heart's electrical signal. 2. Contractile cells: Enable the heart to contract and generate force to pump blood.
71
What are the main components of the cardiac conduction system?
SA node (Sinoatrial node) Internodal pathways AV node (Atrioventricular node) AV bundle (also called the bundle of His) Left and Right bundle branches Purkinje fibers
72
Step 1: Where does the electrical impulse start, and where does it go first?
The electrical impulse is generated by pacemaker cells in the SA node. The signal spreads from the SA node through the atria via specialized internodal pathways, eventually reaching the AV node. This travel time (SA to AV node) takes approximately 50 ms.
73
Step 2: What happens when the signal from the SA node reaches the atrial contractile cells?
The signal triggers the atrial contractile cells, which makes the atria contract. This contraction pumps blood into your left and right ventricles.
74
What happens when the electrical impulse reaches the AV node, and why does this happen?
There is a delay of approximately 100 ms. This delay allows the atria to complete pumping blood before the impulse is transmitted to the AV bundle.
75
Step 4: After the AV node delay, where does the signal travel next?
The signal leaves the AV node and travels down the AV bundle (Bundle of His). The bundle divides the signal into two branches: one branch for the left ventricle and one for the right ventricle.
76
Step 5: How does the signal spread throughout the ventricles to the contractile cells?
The two main bundle branches divide further into the Purkinje fibers. The Purkinje fibers spread the signal through your left and right ventricles.
77
Step 6: What is the result of the signal spreading through the ventricles?
The signal causes the ventricles to contract. The right ventricle pumps blood to your lungs. The left ventricle pumps blood to the rest of your body.
78
What happens after the atria and ventricles contract to complete the heartbeat?
Each part of the system electrically resets itself. The SA node starts the cycle over again in one coordinated motion.
79
Where is smooth muscle located and how is it innervated?
Location: In the walls of hollow organs, such as the gastrointestinal tract, bladder, uterus, vasculature, ureters, bronchioles, and muscles of the eye. Innervation: By the autonomic nervous system (involuntary).
80
What are the five key physical properties of smooth muscle cells?
1. Involuntary. 2. Non-striated. 3. Spindle-shaped. 4. Single nucleus. 5. No sarcomeres (Thick and thin filaments are not organized in sarcomeres).
81
What are the two sub-groups of smooth muscle?
Unitary (or single-unit) smooth muscle. Multiunit smooth muscle.
82
How are Unitary (single-unit) smooth muscle cells connected and what does this allow?
Connection: They have gap junctions between cells (electrically coupled). Function: This allows for the fast spread of electrical activity throughout the organ, followed by a coordinated contraction.
83
How does Multiunit smooth muscle differ from Unitary regarding cell connections?
Multiunit smooth muscle has little coupling (little to no gap junctions) between cells.
84
What are the two main functions of smooth muscle (with examples)?
1. Produce motility: (e.g., to propel urine along the ureter). 2. Maintain tension: (e.g., smooth muscle in the walls of blood vessels).
85
How does the structure of smooth muscle myosin (thick filaments) differ from skeletal muscle?
Structurally similar: (1 pair heavy chains, 2 pairs light chains) but from different genes. Key Difference: Heads are along the entire length, so there is no bare H zone. Result: Cross-bridges can form anywhere along the filament.
86
What is the key regulatory requirement for smooth muscle myosin to interact with actin?
Smooth muscle myosin is unable to interact with actin unless its regulatory light chain is phosphorylated.
87
What proteins are present on the thin filament in smooth muscle, and what key protein is absent?
Present: Actin and Tropomyosin. Absent: Troponin is absent.
88
What protein takes on the primary regulatory role in smooth muscle (in place of troponin)?
Calmodulin (CaM).
89
What is the function of tropomyosin in smooth muscle?
Its function is unknown (unlike in striated muscle where it blocks myosin sites).
90
What structure in smooth muscle is analogous to Z-lines, and what protein is it rich in?
Dense bodies. (Z-lines are lacking). They anchor the thin filaments and are enriched in alpha-actinin.
91
What is the role of intermediate filaments and what are they made of?
Role: They are prominent and link the dense bodies into a cytoskeletal network. Composition: Protein polymers of desmin or vimentin.
92
What protein does smooth muscle lack (that striated has), and what two unique proteins does it contain?
Lacks: Nebulin. Contains: Caldesmon and Calponin (which may regulate contractility).
93
How does the ratio of thick to thin filaments in smooth muscle differ from striated muscle?
Striated: 1 thick is surrounded by 6 thin. Smooth: Small groups of 3-5 thick filaments are surrounded by many thin filaments.
94
How do the filaments create force in smooth muscle?
The myosin cross-bridges pull the actin filaments toward the center of the thick filament, hence developing force.
95
How does the sarcolemma of smooth muscle differ from striated muscle regarding invaginations?
Smooth muscle cells lack T-tubules. Instead, the sarcolemma has many invaginations called caveolae.
96
What are the functions of caveolae?
They increase the surface-to-volume ratio of the cells. They are often closely apposed (next to) the underlying SR. They contain various signaling molecules that regulate Ca²⁺ signaling.
97
What are the two channels on the sarcolemma that cause Ca²⁺ influx (increase cytosolic Ca²⁺)?
Ligand-gated Ca²⁺ channels (LGCC). Voltage-gated Ca²⁺ channels (VGCC).
98
What are the two transporters on the sarcolemma that cause Ca²⁺ efflux (decrease cytosolic Ca²⁺)?
Sarcolemmal Ca²⁺-ATPase (a Ca²⁺ pump). 3Na^{+}/1Ca^{2+} antiporter (also known as NCX).
99
What is the primary role of the Sarcoplasmic Reticulum (SR) in smooth muscle?
It serves as an intracellular reservoir for Ca²⁺.
100
What two channels on the SR cause Ca²⁺ release (increase cytosolic Ca²⁺)?
RyR (Ryanodine Receptor). IP3Rs (IP3-gated Ca²⁺ channels).
101
What pump on the SR causes Ca²⁺ uptake (decrease cytosolic Ca²⁺)?
SERCA (Sarco-Endoplasmic Reticulum Ca²⁺-ATPase).
102
What pathway (shown on Slide 17) leads to the activation of IP3-gated channels?
A Hormone or neurotransmitter binds to its Receptor (R). This activates a G-protein (G). G-protein activates Phospholipase C (PLC). PLC cleaves PIP2 to create IP3. IP3 then binds to and opens the IP3R on the SR.
103
What channel mediates SOCE, and why is it named that way?
Channel: The CRAC channel (Ca²⁺ Release-Activated Ca²⁺ channel). Name: It is named this because it is activated by Ca²⁺ release (depletion) from the E
104
What is "Store-Operated Calcium Entry" (SOCE) and what is its main purpose?
Process: A process of Ca²⁺ influx into the cell that is initiated when the ER/SR Ca²⁺ store is depleted. Purpose: To facilitate refilling of the ER Ca²⁺ store and maintain cellular Ca²⁺ balance.
105
What are the two essential components of the SOC (CRAC) channel and where are they located?
STIM1 (Stromal interaction molecule 1): A single transmembrane protein located in the ER membrane. It senses the Ca²⁺ concentration inside the ER (luminal Ca²⁺). Orai: A structural component of the channel (with 4 transmembrane domains) located in the plasma membrane.
106
What is the state of STIM1 and Orai under resting conditions (when ER Ca²⁺ is high)?
STIM1: Ca²⁺ binds to STIM1, causing it to form a dimer. Orai: Forms either a homodimer or a homotetramer in the plasma membrane.
107
Step 1 (Activation): What happens to STIM1 when ER/SR Ca²⁺ concentration becomes low?
Ca²⁺ dissociates from STIM1. This causes STIM1 proteins to aggregate (cluster together), forming a hexamer. The STIM1 hexamer then translocates (moves) to the ER/SR-plasma membrane junction.
108
Step 2 (Activation): How does aggregated STIM1 open the CRAC channel?
The STIM1 hexamer (at the junction) interacts with Orai. This interaction assembles Orai into an active hexameric Orai channel. This active channel allows Ca²⁺ influx into the cell.
109
What does SOCE sense and not sense?
SOCE senses and responds to changes in luminal Ca²⁺ concentration (inside the ER/SR). It does not depend on, nor does it sense, changes in Ca²⁺ levels in the cytoplasm.
110
How is the CRAC channel inactivated once the ER/SR is refilled?
When ER/SR Ca²⁺ approaches an upper set point... Another protein, TMEM66 (also called SARAF), associates with STIM1. This association inactivates the CRAC channel.
111
What initiates smooth muscle contraction?
An increase in intracellular Ca²⁺ and the subsequent excitation-contraction coupling
112
How does the requirement for extracellular Ca²⁺ differ between smooth and skeletal muscle?
Skeletal Muscle: Does not usually require extracellular Ca²⁺ (relies on AP-induced SR release). Smooth Muscle: Mechanisms involve two Ca²⁺ sources, one of which involves influx from the extracellular pool.
113
What are the two sources of Ca²⁺ for smooth muscle contraction?
The Sarcolemma (regulating influx/efflux from the extracellular Ca²⁺ pool). The Sarcoplasmic Reticulum (SR) (regulating movement between the cytosol and SR pool).
114
What are the two main factors that can alter cytosolic Ca²⁺ in smooth muscle?
Membrane potential (electrical signals). Chemical signals (Hormones and neurotransmitters).
115
Which specific channels are activated by membrane potential vs. chemical signals on the sarcolemma?
Membrane Potential: Activates Voltage-Gated Ca²⁺ Channels (VGCC). Hormones/Neurotransmitters: Activate Ligand-Gated Ca²⁺ Channels (LGCC).
116
Besides the plasma membrane channels, what are the Ligand-gated Ca²⁺ channels on the SR (Slide 19)?
IP₃R (Inositol trisphosphate receptor). RyR (Ryanodine receptor).
117
How does the activation of the contractile apparatus in smooth muscle differ from skeletal muscle?
Skeletal: Fully activated by a single factor: action potential-induced release of Ca²⁺ from the SR. Smooth: Activated by multiple factors (membrane potential, hormones, neurotransmitters) using both SR release and extracellular influx.
118
What is the initial event that initiates smooth muscle E-C coupling?
An elevation of free intracellular Ca²⁺. This Ca²⁺ comes from the activation of channels like VGCC, LGCC, IP3R, or RyR.
119
Since smooth muscle has no troponin, what protein does Ca²⁺ bind to?
Ca²⁺ binds to Calmodulin (CaM).
120
What does the Ca²⁺-Calmodulin complex do next?
The Ca²⁺-Calmodulin complex binds to and activates the enzyme Myosin-Light Chain Kinase (MLCK).
121
What is the key action of the activated MLCK?
MLCK phosphorylates the regulatory light chains of the myosin heads.
122
What is the direct result of this phosphorylation?
Phosphorylation leads to the activation of the Myosin ATPase on the myosin head.
123
What happens once the Myosin ATPase is active?
The phosphorylated myosin heads can now initiate actin-myosin interaction and begin the cross-bridge cycle, leading to contraction.
124
What is the fundamental difference in the E-C coupling mechanism between skeletal and smooth muscle?
Skeletal Muscle: Ca²⁺ binds to Troponin C (on the thin filament/actin). Smooth Muscle: Ca²⁺ binds to Calmodulin (which activates a kinase to act on the thick filament/myosin).
125
Because of this difference, how is skeletal muscle regulation described vs. smooth muscle?
Skeletal Muscle: Thin-filament regulated (because Ca²⁺ regulates the actin filament via Troponin). Smooth Muscle: Thick-filament regulated (because Ca²⁺ regulates the myosin filament via Calmodulin and MLCK).
126
What is the state of an unphosphorylated myosin light chain (at rest)?
There is no myosin ATPase activity, which means there is no cross-bridge activity (Slide 20).
127
What is the state of smooth muscle myosin at rest (Step 1)?
Myosin molecules are energized. They have partially hydrolyzed ATP (to ADP + Pi) to "cock the head". They are ready to interact with actin but require phosphorylation to bind.
128
What triggers the start of the cross-bridge cycle (Step 1) in smooth muscle?
An elevation in intracellular Ca²⁺ activates Calmodulin (CaM). CaM activates MLCK. MLCK phosphorylates myosin light chains, which allows myosin to bind to actin
129
What happens during the "Power Stroke" (Step 2)?
ADP and inorganic phosphate (Pi) are released from the myosin. The cross-bridge undergoes a ratchet action. The thin filament is pulled toward the center of the thick filament, and force is generated.
130
What causes the detachment of myosin from actin (Step 3)?
ATP binds to myosin. This decreases the affinity of myosin for actin. This allows the release of myosin from actin.
131
What is the function of the newly bound ATP (Step 4)?
The energy from the ATP is used to produce a conformational change in the myosin head (i.e., recocking the head). This prepares the cross-bridge for another contraction cycle.
132
How does the speed of cross-bridge cycling in smooth muscle compare to striated muscle?
Although the four basic steps appear to be the same, the kinetics of cross-bridge cycling is much slower for smooth muscle.
133
How long does cross-bridge cycling continue?
It continues (hydrolyzing 1 ATP per cycle) as long as: Cytosolic Ca²⁺ remains elevated. The myosin cross-bridge remains phosphorylated.
134
What general factors can initiate smooth muscle relaxation?
Neurotransmitters, hormones, and drugs that can lower myoplasmic Ca²⁺ levels and thereby relax the smooth muscle.
135
What are the three key mechanisms that actively lower cytosolic Ca²⁺ to begin relaxation?
The ATP-driven SERCA pump moves Ca²⁺ back into the sarcoplasmic reticulum (SR). The sarcolemmal Ca²⁺ pump (Ca²⁺-ATPase) pumps Ca²⁺ out of the cell. The 3Na^{+}/1Ca^{2+} antiporter (NCX) pumps Ca²⁺ out of the cell.
136
What is the first molecular event that occurs after cytosolic Ca²⁺ levels fall?
Ca²⁺ is released from calmodulin.
137
What is the second event, which happens as a direct result of Ca²⁺ leaving calmodulin?
The MLCK (Myosin-Light Chain Kinase) becomes inactive
138
What enzyme becomes dominant when MLCK is inactive, and what is its action?
Myosin Phosphatase (MP) (also called Myosin light chain phosphatase) becomes dominant. Its action is to dephosphorylate the myosin light chain.
139
What is the final mechanical result of myosin dephosphorylation?
The myosin head detaches from actin and the muscle relaxes.
140
How does the speed of smooth muscle relaxation compare to skeletal muscle?
The relaxation in smooth muscle is significantly slower than skeletal muscle relaxation.
141
Where is unitary (single-unit) smooth muscle found in the body?
In the walls of hollow organs, specifically: Gastrointestinal tract Bladder Uterus Ureters.
142
What structural feature allows unitary smooth muscle to contract in a coordinated fashion?
Gap junctions between cells. These allow for the fast spread of electrical activity throughout the organ.
143
How does the scope of contraction in unitary smooth muscle differ from multiunit?
In many cases, the whole organ can contract simultaneously in response to just one action potential .
144
What specific type of activity characterizes unitary smooth muscle (e.g., in the GI tract)?
Spontaneous pacemaker activity. This determines the frequency of contractions (e.g., peristalsis in the GI tract).
145
How does the mechanism of pacemaker activity in smooth muscle differ from the heart?
Heart: Driven by unstable membrane potentials (ion channel fluxes). Smooth Muscle: Likely due to the oscillation of intracellular Ca²⁺ levels.
146
Where in the body is multiunit smooth muscle found?
The iris of the eye. The ciliary muscle of the lens. The vas deferens.
147
Is there electrical coupling between cells in multiunit smooth muscle?
No. There is little or no coupling (gap junctions) between cells.
148
How do the individual fibers of multiunit smooth muscle behave?
Each fiber behaves as a separate motor unit.
149
How is multiunit smooth muscle innervated and controlled?
One autonomic nerve innervates one unit. This unit functions independently from other units
150
What is a Neuromuscular Junction (NMJ) vs. a Neuroeffector Junction (NEJ)?
Neuromuscular Junction (NMJ): The synapse/junction between a motor neuron (Somatic Nervous System) and its effector, a skeletal muscle fiber. Neuroeffector Junction (NEJ): The junction between a postganglionic autonomic neuron (Autonomic Nervous System) and its effector (e.g., smooth muscle, cardiac muscle, or glands).
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What is the first structural difference regarding the organization of the junction?
NMJ: Has a discrete and organized structure. NEJ: The autonomic neurons form diffuse and branching networks over the target tissues.
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What is the second structural difference regarding the postsynaptic receptors?
NMJ: Has a specialized, organized region of receptors called the motor end plate. NEJ: Postsynaptic receptors are widely distributed on the target tissue; there is no specialized region analogous to the motor end plate.
153
What is the third structural difference regarding the site of neurotransmitter release?
NMJ: The sites of neurotransmitter synthesis, storage, and release are the nerve terminals (presynaptic terminal). NEJ: The sites are varicosities (or "beads") that line along the branches of the autonomic neuron.
154
In the NEJ, what structure is analogous to the presynaptic nerve terminal of the NMJ?
The varicosities (the sites of synthesis, storage, and release) are analogous to the presynaptic nerve terminals.
155
What three factors determine the neural regulation of smooth muscle contraction?
The type of innervation (Sympathetic vs. Parasympathetic). The neurotransmitters released. The type and distribution of neurotransmitter receptors on the muscle cell membranes.
156
Sympathetic Regulation: Contraction Mechanism
Agonist: Norepinephrine and Epinephrine. Receptor: $\alpha_{1}$-Adrenergic Receptor (alpha1-AR). Second Messenger: IP3. Response: Contraction (Predominant).
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Sympathetic Regulation: Relaxation Mechanism
Agonist: Norepinephrine and Epinephrine. Receptor: beta2-Adrenergic Receptor (beta2-AR). Second Messenger: cAMP. Response: Relaxation.
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Parasympathetic Regulation: Direct Contraction Mechanism
Agonist: Acetylcholine (ACh). Receptor: Muscarinic receptor on the Smooth Muscle Cell (SMC). Second Messenger: IP3. Response: Direct Contraction.
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Parasympathetic Regulation: Indirect Relaxation Mechanism
Agonist: Acetylcholine (ACh). Receptor: Muscarinic receptor on the Endothelial Cell (EC). Response: Indirect Relaxation.
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Hormonal Regulation: Contraction Agents (Angiotensin II, Vasopressin, Endothelin)
Angiotensin II: via AT-II receptor to IP3 to Contraction. Vasopressin: via Vasopressin receptor to IP3 to Contraction. Endothelin: via Endothelin receptor to IP3 to Contraction.
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Local Regulation: Adenosine Mechanism
Agonist: Adenosine. Receptor: Adenosine receptor. Second Messenger: cAMP. Response: Relaxation.
162
Do all three muscle types have sarcomeres and T-tubules?
Sarcomeres: Skeletal: Yes (striated). Cardiac: Yes (striated). Smooth: No (non-striated). T-tubules: Skeletal: Yes. Cardiac: Yes. Smooth: No (has caveolae instead).
163
How do the three muscle types differ in their use of gap junctions (electrical coupling)?
Skeletal: No. Cardiac: Yes (at intercalated discs, creates a syncytium). Smooth: Yes (for unitary muscle); No (for multiunit muscle).
164
What is the cell shape and nucleus count for each muscle type?
Skeletal: Long, cylindrical, multinucleate. Cardiac: Branched, uninucleate (single nucleus). Smooth: Spindle-shaped, uninucleate (single nucleus).
165
What are the fiber proteins involved in contraction for each muscle type?
Skeletal: Actin, Myosin, Tropomyosin, Troponin. Cardiac: Actin, Myosin, Tropomyosin, Troponin. Smooth: Actin, Myosin, Tropomyosin, (NO Troponin).
166
What is the specific calcium sensor protein that initiates contraction in each type?
Skeletal: Troponin C (on the thin filament). Cardiac: Troponin C (on the thin filament). Smooth: Calmodulin (in the cytoplasm, binds Ca²⁺).
167
What are the calcium sources for contraction in each muscle type?
Skeletal: SR only (Sarcoplasmic Reticulum). Cardiac: SR and ECF (Extracellular Fluid, via CICR). Smooth: SR and ECF (Extracellular Fluid).
168
Is contraction thin-filament or thick-filament regulated for each type?
Skeletal: Thin-filament regulated (Ca²⁺ binds Troponin on actin). Cardiac: Thin-filament regulated (Ca²⁺ binds Troponin on actin). Smooth: Thick-filament regulated (Ca²⁺-Calmodulin activates MLCK to phosphorylate myosin).
169
What type of nervous system controls each muscle type (voluntary/involuntary)?
Skeletal: Voluntary (via Somatic Nervous System - SNS). Cardiac: Involuntary (via Autonomic Nervous System - ANS, hormones). Smooth: Involuntary (via Autonomic Nervous System - ANS, hormones).
