In skeletal muscle the method of excitation contraction coupling relies on the ryanodine

receptor being activated by a domain spanning the space between the T-tubules and the
sarcoplasmic reticulum to produce the calcium transient responsible for allowing contraction.

1. The alpha motor neuron produces an action potential that propagates down its axon to
the neuromuscular junction.
2. The action potential is sensed by a voltage-dependent calcium channel which causes
an influx of Ca2+
ions. This influx results in exocytosis of synaptic vesicles containing acetylcholine.
3. Acetylcholine diffuses across the synapse and binds to nicotinic acetylcholine
receptors on the myocyte, opening them. An influx of Na+
and an efflux of K+
results, depolarizing the cell and generating an end-plate potential.
4. The end-plate potential propagates throughout the myocyte's sarcolemma and into the
T-tubule system.
5. The T-tubule system contains voltage-dependent calcium channels known as
dihydropyridine receptors (DHP) which are activated by the end-plate potential.
6. Rather than releasing calcium from the T-tubules, activated dihydropyridine receptors
transmit the voltage-mediated signal through a mechanical linkage to the ryanodine
 receptors in the sarcoplasmic reticulum. This process involves a conformational
change which allosterically activates type 1 ryanodine receptors.
7. Activated ryanodine receptors then open their channels.
8. Opening of the ryanodine receptors allows a flow of Ca2+
from the sarcoplasmic reticulum into the cytoplasm. In this release, Ca2+
unbinds from the calcium-binding protein called calsequestrin.
9. Ca2+
released from the sarcoplasmic reticulum binds to Troponin C by the actin filaments,
which subsequently causes the troponin complex to pull tropomyosin away from the
myosin binding sites on nearby actin filaments. Myosin cross-bridge binding sites on
the actin filaments are now uncovered.
10. By hydrolysing ATP, myosin can now cycle through attached and detached states to
actin. The attached states are known as "cross bridges" between the actin and myosin
filaments. Activation of this cross-bridge cycling may induce sarcomere shortening
and of the muscle as a whole, but not if the tension is insufficient to overcome the
load imparted on the muscle.
11. Provided a force is developed that exceedes the load, a concentric contraction
initiates. During this contraction, actin's interaction with myosin results in its
movement toward the center of the sarcomere, or M-line, through a series of ATP-
consuming power strokes.
12. A sarcomere will remain contracted in this tightly bound state of rigor unless
sufficient ATP is present to bind with myosin, as a myosin head that is not bound to
actin is bound to ATP.
13. Simultaneously, the sarco/endoplasmic reticulum Ca2+
-ATPase actively pumps Ca2+
back into the sarcoplasmic reticulum where Ca2+
rebinds to calsequestrin.
14. With Ca2+
no longer bound to troponin C, the troponin complex slips position from the open
state to its blocking position. As a consequence of this change, tropomyosin slips into
a position that covers the binding sites on actin.
15. Since cross-bridge cycling is ceasing then any load on the muscle causes the inactive
sarcomeres to lengthen.

Cardiac muscle
In cardiac muscle, the process is dependent on a phenomenon called calcium-induced
calcium release,[2] which involves the conduction of calcium ions into the cell triggering
further release of ions into the cytoplasm (about 75% of calcium present in the cytoplasm
during contraction is released from the sarcoplasmic reticulum).

1. An action potential is initiated by pacemaker cells in the Sinoatrial node or

Atrioventricular node and conducted to all cells in the heart via gap junctions.
2. The action potential travels along the surface membrane into T-tubules (the latter are
not seen in all cardiac cell types) and the depolarization causes Ca2+
to enter the cell via L-type calcium channels (also known as Dihydropyridine
receptors) and possibly sodium-calcium exchanger during the early part of the plateau
phase. This Ca2+
influx causes a small local increase in intracellular Ca2+
.
 3. The increase in Ca2+
is detected by ryanodine receptors in the membrane of the sarcoplasmic reticulum
which releases Ca2+
in a positive feedback physiological response. This positive feedback is known as
calcium-induced calcium release and gives rise to Calcium sparks (Ca2+
sparks [3] ).
4. The spatial and temporal summation of ~30,000 Ca2+
sparks gives a cell-wide increase in cytoplasmic calcium concentration.[4]
5. The cytoplasmic calcium binds to Troponin C, moving the tropomysin complex off
the actin binding site allowing the myosin head to bind to the actin filament. From this
point on the contractile mechanism is essentially the same as for skeletal muscle
(above). Briefly:
6. Using ATP hydrolysis the myosin head pulls the actin filament toward the centre of
the sarcomere.
7. Intracellular calcium is taken up by the sarco/endoplasmic reticulum ATPase pump
back into the sarcoplasmic reticulum ready for the next cycle to begin. Calcium is also
ejected from the cell mainly by the sodium-calcium exchanger and, to a lesser extent,
a plasma membrane calcium ATPase and/or taken up by the mitochondria.[5]
8. Intracellular calcium concentration drops and troponin complex returns over the
active site of the actin filament, ending contraction.

Smooth muscle
Further information: Smooth muscle

It is important to note that contraction of smooth muscle need not require neural inputthat
is, it can function without an action potential. It does so by integrating a huge number of
other stimuli such as humoral/paracrine (e.g. Epinephrine, Angiotensin II, AVP, Endothelin),
metabolic (e.g. oxygen, carbon dioxide, adenosine, potassium ions, hydrogen ions), or
physical stimuli (e.g. stretch receptors, shear stress). This integrative character of smooth
muscle allows it to function in the tissues in which it exists, such as being the controller of
local blood flow to tissues undergoing metabolic changes. In these excitation-free
contractions, then, there of course is no excitation-contraction coupling.

Some stimuli for smooth muscle contraction, however, are neural. All neural input is
autonomic (involuntary). In these the mechanism of excitation-contraction coupling is as
follows: parasympathetic input uses the neurotransmitter acetylcholine. Acetylcholine
receptors on smooth muscle are of the muscarinic receptor type; as such they are
metabotropic, or G-protein / second messenger coupled. Sympathetic input uses different
neurotransmitters; the primary one is norepinephrine. All adrenergic receptors are also
metabotropic. The exact effects on the smooth muscle depend on the specific characteristics
of the receptor activatedboth parasympathetic input and sympathetic input can be either
excitatory (contractile) or inhibitory (relaxing). The main mechanism for actual coupling
involves varying the calcium-sensitivity of specific cellular machinery. However it occurs,
increased intracellular calcium binds calmodulin, which activates myosin light chain kinase
(MLCK). MLCK phosphorylates the regulatory light chains of the myosin heads.
Phosphorylated myosin heads are able to cross bridge-cycle. Thus, the degree to and velocity
of which a whole smooth muscle contracts depends on the level of phosphorylation of myosin
heads. Myosin light chain phosphatase removes the phosphate groups from the myosin heads,
thus ending cycling (and leaving the muscle in latch-state).