Difficulty: Intermediate to Advanced | Prerequisites: Parts 1 and 2 of these notes (cytoskeleton, myosin, sarcomere structure), basic understanding of membrane potential and action potentials.
You now know that myosin pulls on actin to shorten the sarcomere, but something has to tell the muscle when to contract. That something is calcium. This section covers how an electrical signal (an action potential) is converted into a mechanical response (contraction), a process called excitation-contraction (EC) coupling. The pathway is different in skeletal, cardiac, and smooth muscle, and knowing those differences is one of the most exam-tested topics in this chapter. You should be comfortable with membrane potential, action potentials, and the troponin-tropomyosin system from Part 2 before starting here.
An action potential travels along the muscle membrane and into T-tubules, triggering calcium release from internal stores (the sarcoplasmic reticulum). Calcium binds to troponin, which moves tropomyosin out of the way and lets the cross-bridge cycle begin. Skeletal muscle uses depolarisation-induced Ca2+ release (DHPR physically opens RyR). Cardiac muscle uses Ca2+-induced Ca2+ release (extracellular Ca2+ entering through DHPR triggers RyR). Smooth muscle uses calmodulin instead of troponin.
Excitation-contraction (EC) coupling
The process that links an electrical signal (depolarisation of the muscle membrane) to a mechanical response (contraction via the cross-bridge cycle). Think of it as the translation step between "nerve says go" and "muscle pulls."
Sarcolemma
The plasma membrane of a muscle cell. In simple terms, the sarcolemma is to a muscle cell what the plasma membrane is to any other cell.
T-tubule (transverse tubule)
An infolding of the sarcolemma that plunges deep into the muscle cell, allowing action potentials to reach the interior. Think of it as a tunnel that carries the electrical signal to the centre of a very large cell.
Sarcoplasmic reticulum (SR)
A specialised endoplasmic reticulum in muscle cells that stores calcium ions bound to the protein sequestrin. The terminal cisternae of the SR sit next to T-tubules and release Ca2+ on demand.
DHPR (dihydropyridine receptor)
A voltage-gated Ca2+ channel in the T-tubule membrane. In skeletal muscle, it is physically connected to RyR. In cardiac muscle, it allows extracellular Ca2+ to enter the cell.
RyR (ryanodine receptor)
A Ca2+ release channel in the SR membrane. Opens to flood the cytoplasm with calcium and trigger contraction. Named because it binds the plant alkaloid ryanodine. Caffeine can also directly activate RyR.
SERCA
A Ca2+ ATPase pump in the SR membrane that actively pumps calcium back into the SR to end contraction. In simple terms, SERCA is the "off switch" for muscle contraction.
NaCaX (Na+/Ca2+ exchanger)
A secondary active transporter in the sarcolemma that removes Ca2+ from the cytoplasm by exchanging it for Na+.
Sequestrin (calsequestrin)
A calcium-binding protein inside the SR that allows the SR to store large quantities of Ca2+.
Parvalbumin
A cytosolic calcium-binding protein that buffers (chelates) free Ca2+ in the cytoplasm, helping to accelerate relaxation.
Ca2+-induced Ca2+ release
The mechanism used in cardiac muscle. A small amount of extracellular Ca2+ enters through DHPRs and triggers the opening of RyR channels in the SR, releasing a much larger flood of stored Ca2+. A positive feedback loop.
Depolarisation-induced Ca2+ release
The mechanism used in skeletal muscle. Depolarisation causes a conformational change in DHPR, which is physically linked to RyR, mechanically opening the SR channel without requiring extracellular Ca2+ entry.
Neurogenic
Muscle whose contraction is initiated by a nerve signal (neurotransmitter release). Skeletal muscle is neurogenic.
Myogenic
Muscle whose contraction is initiated within the muscle itself, typically by pacemaker cells. Cardiac muscle is myogenic.
Pacemaker cell
A cardiac cell with an unstable resting membrane potential that spontaneously depolarises and fires action potentials, setting the rhythm for the heart.
Plateau potential
The prolonged phase of the cardiac action potential caused by a balance between excitatory (Ca2+) and inhibitory (K+) currents. Essential for coupling the action potential to the full duration of cardiac contraction.
Effective refractory period
The period during a cardiac action potential when the cell cannot fire another AP. Prevents the heart from tetanising (sustained contraction), which would be fatal.
Calmodulin
A calcium-binding regulatory protein used in smooth muscle (instead of troponin). When Ca2+ binds to calmodulin, it removes the inhibitory protein caldesmon from actin and also promotes phosphorylation of myosin to increase ATPase activity.
Caldesmon
A protein in smooth muscle that blocks the myosin-binding site on actin at rest. In simple terms, caldesmon does in smooth muscle what tropomyosin does in striated muscle.
The sequence from signal to contraction follows three steps:
Depolarisation of the sarcolemma (the muscle plasma membrane)
Elevation of intracellular Ca2+
Contraction via the sliding filament / cross-bridge cycle
In skeletal muscle, the process begins when acetylcholine (ACh) is released from a motor neuron, binds to nicotinic ACh receptors on the sarcolemma (non-selective cation channels with a reversal potential of 0 mV, making them excitatory), and depolarises the membrane. The action potential then propagates along the sarcolemma and down into T-tubules.
At rest, cytoplasmic [Ca2+] is low (100 to 200 nM). Tropomyosin, held in place by troponin, blocks the myosin-binding sites on actin. No cross-bridges can form.
When cytoplasmic [Ca2+] rises:
Ca2+ binds to TnC (the calcium-binding subunit of troponin)
The troponin-tropomyosin complex shifts position, exposing the myosin-binding sites on actin
Myosin binds to actin and the cross-bridge cycle begins
Cycles continue as long as calcium is present
The cell relaxes when the sarcolemma repolarises and intracellular calcium returns to resting levels. Three mechanisms remove Ca2+ from the cytoplasm:
Ca2+ ATPase (SERCA) in the SR membrane pumps Ca2+ back into the SR
Ca2+ ATPase in the sarcolemma pumps Ca2+ out of the cell
Na+/Ca2+ exchanger (NaCaX) in the sarcolemma uses the Na+ gradient to export Ca2+
Parvalbumin, a cytosolic Ca2+-binding protein, buffers free Ca2+
Once Ca2+ dissociates from troponin, tropomyosin slides back over the myosin-binding sites and contraction stops.
Key rule of thumb: channels bring Ca2+ IN, transporters move Ca2+ OUT.
Skeletal muscle = neurogenic. Depolarisation is triggered by ACh released from motor neurons at the neuromuscular junction.
Cardiac muscle = myogenic. Depolarisation originates spontaneously in pacemaker cells, which have an unstable resting membrane potential that drifts toward threshold via hyperpolarisation-activated cation channels (funny channels / HCN channels).
Action potentials travel along the sarcolemma and signal contraction in both muscle types, but the shape of the AP differs.
Skeletal muscle AP:
Na+ channels open (depolarisation), then close
Voltage-gated Ca2+ channels open briefly
K+ channels open (repolarisation)
Short duration, fast repolarisation
Can fire another AP while still contracting, allowing summation of force
Cardiac muscle AP:
Na+ channels open (depolarisation), then close
Voltage-gated Ca2+ channels open and stay open, creating a plateau potential (a tug-of-war between inward Ca2+ current and outward K+ current)
K+ channels eventually win and repolarise the cell
Long duration, slow repolarisation
Effective refractory period prevents a second AP during contraction, which protects the heart from tetanus (sustained contraction that would stop it pumping)
Ion gradients are re-established by Na+/K+ ATPase and Ca2+ ATPase.
This is one of the most important concepts in the chapter.
Cardiac muscle: Ca2+-induced Ca2+ release
Depolarisation opens DHPRs in the T-tubule membrane
Extracellular Ca2+ flows in through DHPRs
This small Ca2+ influx triggers RyR channels in the SR to open (positive feedback)
A large flood of Ca2+ is released from SR stores
DHPR and RyR are not physically connected
If you remove extracellular Ca2+, cardiac muscle cannot contract
Skeletal muscle: depolarisation-induced Ca2+ release
Depolarisation causes a conformational change in the DHPR voltage sensor
DHPR and RyR are physically associated (linked protein to protein across the T-tubule and SR membranes)
The voltage sensor movement in DHPR mechanically opens RyR
Ca2+ floods out of the SR
Extracellular Ca2+ entry is not required for contraction
If you remove extracellular Ca2+, skeletal muscle can still contract
RyR is not intrinsically a voltage-gated channel, but in skeletal muscle it behaves as one because of its physical association with DHPR.
The classic experiment to distinguish the two mechanisms: remove extracellular calcium. Cardiac muscle stops contracting; skeletal muscle does not.
Muscle cells are enormous. A voltage-gated Ca2+ channel on the surface membrane would be too far from the myofibrils deep inside. T-tubules solve this problem.
T-tubules are invaginations of the sarcolemma, continuous with the plasma membrane
They carry the action potential deep into the cell interior
They bring the depolarisation signal directly to where the SR stores calcium
A modified endoplasmic reticulum that stores Ca2+ bound to sequestrin
Terminal cisternae are the expanded ends of the SR that sit next to T-tubules, maximising the Ca2+ storage capacity near the release site
T-tubules and terminal cisternae are physically adjacent, forming triads (in skeletal muscle) or dyads (in cardiac muscle)
DHPR (dihydropyridine receptor): voltage-gated Ca2+ channel in the T-tubule / sarcolemma
RyR (ryanodine receptor): Ca2+ release channel in the SR membrane; caffeine can directly activate it
Ca2+ ATPase in the sarcolemma (pumps Ca2+ out of the cell)
SERCA (Ca2+ ATPase in the SR membrane, pumps Ca2+ back into stores)
NaCaX (Na+/Ca2+ exchanger in the sarcolemma)
ACh released from motor neuron at the neuromuscular junction
ACh binds to nicotinic ACh receptors on the sarcolemma
Action potential propagates along the sarcolemma and down T-tubules
AP activates DHPR (voltage sensor conformational change)
DHPR mechanically opens RyR (depolarisation-induced Ca2+ release)
Ca2+ floods from SR into the cytoplasm
Ca2+ binds to TnC on troponin, which shifts tropomyosin
Myosin-binding sites on actin are exposed
Cross-bridge cycle begins, sliding filament, muscle contraction
Ca2+ is removed by SERCA, Ca2+ ATPase, and NaCaX; muscle relaxes
Smooth muscle differs from striated muscle in several important ways.
No sarcomeres and no striations; thick and thin filaments are scattered and attached to the membrane at adhesion plaques
No T-tubules and minimal SR
Cells are much smaller
Often connected by gap junctions, allowing them to function as a single unit
Can contract in all dimensions (not just along one axis)
No Nav channels
Smooth muscle is regulated by nerves, hormones, and physical conditions (such as stretch of the vessel wall). The calcium-sensing machinery is different from striated muscle.
Smooth muscle does not have troponin
At rest, the protein caldesmon is bound to actin and blocks the myosin-binding site (analogous to tropomyosin in striated muscle)
When the cell is stimulated, intracellular Ca2+ rises
Ca2+ binds to calmodulin
Calmodulin binds caldesmon and removes it from actin, exposing the myosin-binding sites
Cross-bridges form and contraction occurs
Calmodulin also promotes phosphorylation of myosin light chains, increasing myosin ATPase activity
Smooth muscle contractions are slow and prolonged, well suited to maintaining tension in blood vessel walls and moving material through the digestive tract.
Feature | Skeletal | Cardiac | Smooth |
|---|---|---|---|
Excitation | Neurogenic (voluntary) | Myogenic (involuntary) | Nerves, hormones, stretch |
Striations | Yes (sarcomeres) | Yes (sarcomeres) | No |
AP duration | Short, fast repolarisation | Long, plateau + refractory period | Variable |
EC coupling | Depolarisation-induced Ca2+ release | Ca2+-induced Ca2+ release | Ca2+ / calmodulin / caldesmon |
Extracellular Ca2+ needed? | No | Yes | Depends on subtype |
T-tubules | Yes | Yes | No |
Caffeine directly activates ryanodine receptors (RyR), which is one reason it can cause muscle twitching and increased heart rate at high doses. Dihydropyridine drugs (e.g. nifedipine, amlodipine) block DHPR channels and are widely used to treat high blood pressure and angina by reducing calcium entry into cardiac and smooth muscle cells. Understanding the difference between Ca2+-induced and depolarisation-induced Ca2+ release also matters clinically: drugs that lower extracellular Ca2+ will impair cardiac contraction but leave skeletal muscle largely unaffected.
Students often think Ca2+-induced Ca2+ release and depolarisation-induced Ca2+ release are the same thing. They are mechanistically different: cardiac muscle needs extracellular Ca2+ to trigger SR release (positive feedback via RyR), while skeletal muscle uses a direct physical linkage between DHPR and RyR.
Students sometimes believe that removing extracellular calcium stops all muscle contraction. It stops cardiac contraction but not skeletal contraction, because skeletal muscle relies on depolarisation-induced release from internal stores.
Students often confuse the plateau potential with a prolonged depolarisation. The plateau is a balance between inward Ca2+ current and outward K+ current, not simply a failure to repolarise.
Students sometimes think smooth muscle uses troponin. It does not. Smooth muscle uses the calmodulin-caldesmon system instead.
Students often assume pacemaker cells have a stable resting membrane potential. They do not; the resting potential drifts continuously toward threshold, which is what makes them pace.
⚠️ The difference between Ca2+-induced Ca2+ release (cardiac) and depolarisation-induced Ca2+ release (skeletal) is one of the most commonly tested concepts in this chapter.
⚠️ Know the classic experiment: remove extracellular Ca2+. Cardiac muscle stops contracting; skeletal muscle does not.
⚠️ Be able to list the full EC coupling sequence in skeletal muscle from ACh release through to relaxation (the 10-step sequence).
⚠️ Know that DHPR and RyR are physically associated in skeletal muscle but not in cardiac muscle.
⚠️ Know why the cardiac AP has a plateau potential and an effective refractory period (prevents tetanus).
⚠️ Be able to compare skeletal, cardiac, and smooth muscle on excitation type, AP shape, EC coupling mechanism, and structural features.
⚠️ Know that smooth muscle uses calmodulin and caldesmon instead of troponin and tropomyosin.
⚠️ Channels = Ca2+ IN (DHPR, RyR). Transporters = Ca2+ OUT (SERCA, Ca2+ ATPase, NaCaX).
True or false: Cardiac muscle uses depolarisation-induced Ca2+ release. (False. Cardiac muscle uses Ca2+-induced Ca2+ release.)
Fill in the blank: The calcium-binding protein on the thin filament in striated muscle is ______. (TnC, the calcium-binding subunit of troponin.)
True or false: Removing extracellular calcium prevents skeletal muscle from contracting. (False. Skeletal muscle can still contract because it uses depolarisation-induced release from internal SR stores.)
Fill in the blank: In smooth muscle, Ca2+ binds to ______ instead of troponin. (Calmodulin.)
True or false: Cardiac pacemaker cells have a stable resting membrane potential. (False. Their resting potential drifts continuously toward threshold.)
Q: Describe the difference between Ca2+-induced Ca2+ release and depolarisation-induced Ca2+ release. Which muscle type uses each?
A: In Ca2+-induced Ca2+ release (cardiac muscle), extracellular Ca2+ entering through DHPR channels triggers RyR to open, releasing stored Ca2+ from the SR. In depolarisation-induced Ca2+ release (skeletal muscle), depolarisation causes a conformational change in DHPR, which is physically linked to RyR. The voltage sensor movement in DHPR mechanically opens RyR without requiring extracellular Ca2+ entry.
Q: You remove all extracellular calcium from the bathing solution around an isolated cardiac myocyte and an isolated skeletal myocyte, then stimulate both. What happens to each and why?
A: The cardiac myocyte stops contracting because it depends on extracellular Ca2+ to trigger RyR opening (Ca2+-induced Ca2+ release). The skeletal myocyte continues to contract because its DHPR is physically coupled to RyR, so depolarisation alone opens the SR channel and releases internal Ca2+ stores.
Q: Why does the heart have an effective refractory period and what would happen without it?
A: The effective refractory period prevents the cardiac cell from firing a second action potential during contraction. Without it, the heart could tetanise (sustain a continuous contraction like skeletal muscle can), which would stop it from relaxing and refilling with blood between beats.
Q: Name three mechanisms that remove Ca2+ from the cytoplasm to end contraction.
A: (1) SERCA pumps Ca2+ back into the SR. (2) Ca2+ ATPase in the sarcolemma pumps Ca2+ out of the cell. (3) Na+/Ca2+ exchanger (NaCaX) in the sarcolemma exports Ca2+ using the Na+ gradient. Parvalbumin also buffers free cytosolic Ca2+.
Q: How does smooth muscle contraction differ from striated muscle contraction at the molecular level?
A: Smooth muscle lacks troponin. Instead, at rest, caldesmon blocks the myosin-binding sites on actin. When Ca2+ rises, it binds to calmodulin, which removes caldesmon from actin, allowing cross-bridges to form. Calmodulin also promotes phosphorylation of myosin light chains, increasing myosin ATPase activity. There are no sarcomeres, no T-tubules, and minimal SR.
This material ties directly back to Parts 1 and 2: the troponin-tropomyosin switch introduced in Part 2 is the target of the calcium signalling covered here, and the cytoskeletal motor proteins from Part 1 are the same molecular machines at work in the sarcomere. EC coupling also connects to the broader neuroscience and signal transduction parts of the course, since the neuromuscular junction, acetylcholine receptors, and voltage-gated ion channels all appear in the nervous system material. If you continue into cardiovascular physiology, the cardiac pacemaker, plateau potential, and effective refractory period return as central concepts.
excitation-contraction coupling, EC coupling, sarcolemma, T-tubule, transverse tubule, sarcoplasmic reticulum, SR, terminal cisternae, triad, dyad, DHPR, dihydropyridine receptor, RyR, ryanodine receptor, SERCA, NaCaX, Na+/Ca2+ exchanger, Ca2+ ATPase, calsequestrin, sequestrin, parvalbumin, calcium imaging, Ca2+-induced Ca2+ release, depolarisation-induced Ca2+ release, neurogenic, myogenic, pacemaker cell, funny channel, HCN channel, plateau potential, effective refractory period, acetylcholine, ACh receptor, neuromuscular junction, troponin, TnC, TnI, TnT, tropomyosin, calmodulin, caldesmon, smooth muscle, cardiac muscle, skeletal muscle, action potential, depolarisation, repolarisation, voltage-gated calcium channel, caffeine, nifedipine, amlodipine