Department of Physiology: Nerves and Muscles Physiology-Review & Illustrations

Resting membrane potential (RMP) (Equilibrium Potentials)

Is the potential difference between the inner and outer surface of a biological membrane during rest or inactivity at which the forces of concentration gradient and electrical gradient balance. RMP has a negative value which means that the inner side of the membrane is more negative relative to the outside of the membrane. It is due to:

(1) Mainly it is due to passive outward diffusion of K⁺ ions (diffusion potential).

(2) To less extent it is due to electrogenic pump (Na⁺-K⁺ pump).

The action potential of the nerve and skeletal muscle fiber (figure):

Action potential (also called impulse in the nerve fiber) is a rapid and transient change in the membrane potential that can be transmitted across the surface of an excitable cell. The stages of an action potential are as fallow:

[1] Resting stage: which represents a RMP before the action potential occurs.

[2] Initiation of an action potential (generation of graded potential): Any event (chemical, mechanical, electrical stimulation) that increases the membrane permeability to the Na⁺ ions by opening of chemical-gated, or mechanical-gated, or voltage-gated Na⁺ channels will lead to Na⁺ influx and consequently an initial rise in the membrane potential toward the zero level. If this initial rise in membrane potential is rapid and enough in magnitude, it may approach a critical level called the threshold level at which action potential will be generated.

[3] Depolarization stage of action potential: When the membrane potential reaches the threshold level, the potential across the membrane rises suddenly and rapidly in the positive direction approaching zero or may overshoots and become positive. The cause of this depolarization is due to sudden opening of voltage-gated Na⁺ channels which their opening depend on the voltage across the membrane (threshold level).

[4] Repolarization stage of action potential: In which the normal resting membrane-polarizing state is re-established. The causes of repolarization are:

Closure of voltage-gated Na⁺ channels.
Opening of voltage-gated K⁺ channels.
Electrogenic pump (Na⁺-K⁺ ATPase pump).

Graded potential versus Action potential

Degree of excitability:

Highly excitable tissue is when the value of RMP of it is very near to the threshold value for the action potential.
Less excitable tissue is when the value of RMP of it is away from the threshold value for the action potential. Low intensity stimulus is required for the first and high intensity stimulus is required for the second to initiate an action potential.

Effect of ECF Na⁺, Ca²⁺ and K⁺ ions concentration on excitability level:

Hyponatremia: Decreasing the external Na⁺ ion concentration decreases the size of the action potential but has little effect on the excitability level.
Hypercalcemia decreases the excitability of the nerve fiber by increasing the threshold level value. Hypocalcemia increases the excitability of nerve fiber by decreasing the threshold level value.
Mild hyperkalemia (5.5-5.9 mmol/L) → Increases excitability. A mild increase in the concentration of extracellular K⁺ (mild hyperkalemia) causes the resting potential of nerve fibers to be less negative (partially depolarized). As a result, the threshold potential is reached with a less intense stimulus than usual.
Moderate (6.0-6.4 mmol/L) to severe (>6.5 mmol/L) hyperkalemia → Decrease excitability of nerve fiber by increasing the threshold level due to inactivation of some the voltage-gated sodium channels that are inactivated at higher extracellular K⁺ concentration

The action potential of the cardiac and smooth muscle fibers (figure): The action potential of cardiac muscles (atria, ventricles, and Purkinje fibers) and some smooth muscles is different from that seen in the skeletal muscles and nerve fibers by the following:

The presence of plateau near the peak of the spike for few msec before repolarization begins due to the presence of voltage-gated Ca²⁺ channels.
The duration of action potential is much longer due to the presence of the plateau.
In some smooth muscle fibers, the spike potential and the plateau are both due to voltage-gated Ca²⁺ channels rather than voltage-gated Na⁺ channels.

In cardiac muscles, repolarization is achieved by:

Closure of voltage-gated Na⁺ channels.
Closure of voltage-gated Ca²⁺ channels.
Activation of voltage-gated K⁺ channels.
Na⁺-K⁺ pump.
The Ca²⁺ pump.

Re-establishment of the normal resting membrane potential: This is achieved by Na⁺-K⁺ pump and by Ca²⁺pump.

Propagation of the action potential: An action potential (nerve impulse) elicited at any one point on an excitable membrane usually excites adjacent portion of the membrane, resulting in propagation of the action potential to all directions away from the stimulus until the entire membrane has become depolarized. This is because the inflow of Na⁺ ions through the first depolarized point of the membrane will create electro-positivity on the inner side of the first depolarized point and also on the adjacent resting membrane points. This will change the membrane potential at the adjacent points to the threshold voltage value for initiating another new action potential adjacent to the first one, which in turn initiates another action potential, causing progressively more and more depolarization.

Action potential duration & velocity

Rhythmicity (also called automaticity or spontaneous repetitive discharge) of certain excitable cells:

Rhythmical cell is the cell that can generate action potential spontaneously (without external stimulus) and repetitively (repeats itself). The characteristics of cell membrane of the excitable cell are:

The threshold level for stimulation is low.
The cell membrane is more permeable to Na⁺/or Ca²⁺ ions than non-rhythmical cell.
The cell membranes show cyclic increase and decrease of the pumping of Na⁺ (by Na⁺-K⁺ ATPase pump) and Ca²⁺ ions (by Ca⁺⁺ ATPase pump) outward through the cell membrane. This cyclic increase and decrease activity of Na⁺ or Ca²⁺ pump will lead to generate a continuous change in resting membrane potential locally. This local wave-like change in resting membrane potential is of two types: Slow wave potential or pacemaker wave potential.

The Refractory Period:

It is the period of time during which the second action potential is difficult (Relative refractory period) or cannot occur (Absolute refractory period) in an excitable fiber as long as the membrane is still depolarized from the preceding action potential. This period can be of two types:

Absolute refractory period: This period corresponds the period of depolarization and about one-third of repolarization. This is because the voltage-gated Na⁺ channels are still in an inactive state (closed) due to the preceding action potential.
Relative refractory period: This period follows the absolute refractory period and last from the end of the first 1/3 of repolarization to the end of hyperpolarization. During this time, application of stronger than normal stimuli can excite the fiber. The causes of this relative refractory period are:

A. During this time some the voltage-gated Na⁺ channels still have not been reversed from their closed state.

B. The voltage-gated K⁺ channels are usually wide open at this time, so any tendency for Na⁺ ions to flow in is associated with K⁺ions efflux.

C. In addition, the end of this period of time is associated with the state of hyperpolarization that makes it more difficult to stimulate the fiber.

Myelination is important for the following reasons:

It increases the excitability of the nerve fiber.
It speeds up the conduction velocity of action potential along the nerve fiber by jumping from node to node. This is called saltatory conduction. This mechanism increases the velocity of nerve transmission in myelinated fiber of an average of 5-50 times.
Conserves energy for the axon, for only the nodes depolarize.

Factors that affect the conduction velocity:

Myelination, myelinated nerve is about 50 times faster.
Axon diameter, conduction velocity increases directly with axon diameter.
Temperature.

Electrical properties of a nerve (nerve trunk) action potential:

Does not obey the all or none law: This mean that as the stimulus intensity increases, the amplitude of action potential is increased.
Generation of compound action potential: This means that as the stimulus intensity increases, the duration of action potentials is increased with the appearance of multiple peaks.

Glia: In the peripheral nervous system there are two types of glial cells:

[a] Schwann cells.
[b] Satellite cells.

In the central nervous system (CNS), there are four main types of glia:

[a] Microglia.
[b] Oligodendrogliocytes.
[c] Ependymal cells.
[d] Astrocytes which are found throughout the brain (fibrous astrocytes in the white matter and protoplasmic astrocytes in the gray matter). The main functions of astrocytes are:

Astrocytes contribute in the formation of the Blood-brain barrier (BBB).
They also send processes that envelop synapses and the surface of nerve cells.
They produce substances that are trophic to neurons.
They help maintain the appropriate concentration of substances in the interstitial fluid by taking up K⁺ ions and neurotransmitters (glutamate and GABA). Without rapid K⁺ reuptake, [K⁺] increases and depolarizes neuronal resting membrane potentials.
To provide neurons with lactate as an energy source.
To synthesize neurotransmitter precursors for neurons (e.g., glutamine synthesis for glutaminergic neurons).

Classification of nerve fibers:

[i] The fibers can be classified according to their conduction velocity into the following general types:

1. Type A fibers: They are the typical myelinated fibers of spinal nerves that conduct impulses at high velocities (6-120 m/sec). According to the conduction velocity, they subdivided in descending order into:

Alpha (α) fibers: Motor and sensory fibers of skeletal muscles.
Beta (β) fibers: Sensory from skeletal muscles, also carry fine touch, pressure and vibration.
Gamma (γ) fibers: Motor to intrafusal muscle fiber.
Delta (δ) fibers: They carry fast pain, touch, pressure, and cold temperature.

2. Type B fiber: They are myelinated fibers that conduct impulses at lower velocity than type A nerve fibers. They are the preganglionic fibers of the autonomic nervous system

3. Type C fibers: They are very small unmyelinated nerve fibers that conduct impulses at low velocities. They are postganglionic fibers in the ANS, also carry slow pain, warmth and cold temperature, touch, pressure, itch).

NOTE: The susceptibility of the fibers to pressure, hypoxia, and local anesthesia is shown in the table.

[ii] The fibers can be classified according to the direction in which they conduct impulses:

Sensory, or afferent neurons, conduct impulses from sensory receptors into the CNS.
Motor, or efferent neurons conduct impulses out of the CNS to effector organs (muscles and glands). There are two types of motor neurons: somatic (responsible for both reflex and voluntary control of skeletal muscles ) and autonomic (innervate the involuntary effectors—smooth muscle, cardiac muscle, and glands).
Interneurons, are located entirely within the CNS and serve the associative, or integrative functions of the nervous system.

[iii] The structural classification of neurons is based according to the number of processes that extend from the cell body of the neuron.

Unipolar neurons have a single short process that branches like a T to form a pair of longer processes. Sensory neurons are unipolar. One of the branched processes receives sensory stimuli and produces nerve impulses; the other delivers these impulses to synapses within the brain or spinal cord. Anatomically, the part of the process that conducts impulses toward the cell body can be considered a dendrite, and the part that conducts impulses away from the cell body can be considered an axon. Functionally, however, the two branched processes behave as a single long axon; only the small projections at the receptive end of the process function as typical dendrites.
Bipolar neurons have two processes, one at either end; this type is found in the retina of the eye.
Multipolar neurons, the most common type, have several dendrites and one axon extending from the cell body; motor neurons are good examples of this type.

Transmission of signal or impulse across the synapse: When the action potential depolarizes the terminal, large number of voltage-gated Ca²⁺ channels at the terminal membrane open and consequently large number of Ca²⁺ ions flow into the terminal. The influx of Ca²⁺ ions into the terminal initiates the process of exocytosis of the terminal vesicles, which fuse with the presynaptic membrane and release its content of the neurotransmitter. The quantity to transmitter substance that is released into the synaptic cleft is directly related to the number of Ca²⁺ ions that enter the terminal. The transmitter then diffuses across the synaptic cleft and interacts with receptors at the postsynaptic membrane. The result of interaction is one of the following:

[1] May leads to open the neurotransmitter-gated Na⁺ or Ca²⁺ channels that allow Na⁺ or Ca²⁺ ions to pass through the cell membrane resulting in bringing the membrane potential of the postsynaptic membrane to threshold level. This local change in membrane potential is a graded potential and is called excitatory postsynaptic potential (EPSP). Summation of many EPSPs causes change in the postsynaptic cell membrane potential to the threshold level with consequent generation of action potential and excitation of postsynaptic cell. When summation of EPSPs has not raised high enough to reach the threshold for eliciting an action potential, the neuron is said to be facilitated. That is its membrane potential is nearer to the threshold for firing than normally but not yet to the firing level. When the membrane potential inside the soma rises high enough, i.e. about –45 mV, action potential begins in the postsynaptic neuron at the axon hillock, and not on the soma membrane adjacent to the excitatory synapses. The main reason for this is that the soma has relatively few voltage-gated Na⁺ channels in its membrane, which are less than enough required to elicit an action potential. On the other hand, the membrane of the axon hillock has seven times as great a concentration of voltage-gated Na⁺ channels and therefore can generate an action potential.

[2] May lead to open neurotransmitter-gated Cl^-or K⁺-channels that allow mainly Cl^- or K⁺ ions to pass through with consequent hyperpolarization of the membrane toward the Cl^- or K⁺ ion equilibrium potential (-90 mV) resulting in inhibition of cell due to hyperpolarization of the membrane. This local change in membrane potential (hyperpolarization) is a graded potential and is called inhibitory postsynaptic potential (IPSP). The inhibitory neurotransmitters are γ-aminobutyric acid (GABA) and glycine.

[3] May lead to activate enzymes, which in turn activates an internal metabolic system “second messenger” of the cell resulting in either increase or decrease the number of receptors or prolonged changes in postsynaptic neurons. Such changes can alter the reactivity of the synapse for minutes, days, months or even years (synaptic plasticity). Therefore, transmitter substances that cause such effects are called synaptic modulators.

Types of summation at postsynaptic membrane:

Spatial summation: In which many presynaptic terminals that end (converge) on the membrane of a single soma are stimulated at the same time.
Temporal summation: In which presynaptic terminals fire repetitively in rapid succession.

Removal of the transmitter from the synapse: After the transmitter agent binds with the receptors, is rapidly removed from the synaptic cleft. This is achieved in three different ways:

By diffusion of the transmitter out of the cleft into the surrounding fluids.
By enzymatic destruction within the cleft itself. For instance, in the case of acetylcholine, the enzyme cholinesterase is present in the cleft and inactivates this transmitter substance.
By active transmitter re-uptake back into the presynaptic terminal itself and are then reused again and again. This is called transmitter re-uptake.

Fatigue of synaptic transmission: When excitatory synapses are repetitively stimulated at a rapid rate, the number of discharges by postsynaptic neuron is at first very great, but it becomes progressively less in succeeding milliseconds or second. The mechanism of fatigue is mainly due to exhaustion of the stores of the transmitter substance in the synaptic terminal.

Effect of acidosis and alkalosis on synaptic transmission: Alkalosis greatly increases neuronal excitability due to the reduction in the free ECF Ca²⁺ ions concentration (hypocalcaemia) (but not the total Ca²⁺ concentration), which modulates the activity of voltage-gated Na⁺ channels. A rise in arterial pH from normal of 7.4 to about 7.8 often causes cerebral convulsions because of increased excitability due to the decrease in the free ECF Ca²⁺ ions concentration (hypocalcaemia) (but not the total Ca²⁺ concentration), which modulate the activity of voltage-gated Na⁺ channels of the neurons. A fall in pH from 7.4 to below 7.0 usually causes greatly decreases neuronal excitability due to the increase in the free ECF Ca²⁺ ions concentration (hypercalcaemia) (but not the total Ca²⁺ concentration), which modulate the activity of voltage-gated Na⁺ channels and often causes comatose state as it occurs in diabetic or uremic acidosis.

Synaptic plasticity: It is the changes in the synaptic functions as a result of the history of discharging at a synapse, i.e. synaptic conduction can be strengthened or weakened on the basic of past experience. These changes can be presynaptic or postsynaptic. These changes are of the following forms:

1. Presynaptic facilitation, there is an excitatory interneuron ending on the presynaptic neuron. The release of serotonin from the interneuron causes increased Ca⁺⁺ influx into the presynaptic terminal to result in greater release of neurotransmitter. This leads to increased excitability of postsynaptic neuron.

2. Short-term post-tetanic potentiation: It is the production of short (few sec to few hours) postsynaptic potentials as a result of a brief (tetanizing) train of stimuli in the presynaptic neuron. It is due to the buildup of excess Ca²⁺ ions in the presynaptic neuron and consequently a continuous release of neurotransmitter.

3. Long-term post-tetanic potentiation (LTP): It is the production of long (days) postsynaptic potentials as a result of a brief (tetanizing) train of stimuli in the presynaptic neuron. It is due to the buildup of excess Ca²⁺ ions in the postsynaptic neuron and consequently alters the phosphorylation of intracellular proteins in a way that leads to greater EPSPs in response to stimulation of presynaptic terminals.

4. Long term depression ( LTD) is opposite to that of LTP and occurs in all the regions of the brain. It occurs when there is weak stimulation of presynaptic neurons, which reduces Ca⁺⁺ influx into the presynaptic terminal. LTD is said to be associated with learning process similar to LTP.

5. Postsynaptic habituation: It is gradual decrease of postsynaptic response to a continuous presynaptic stimulation. It is due to decrease of the presynaptic neurotransmitter release as a result of inactivation of voltage-gated Ca²⁺ channels at the terminal button membrane with consequent reduction of Ca²⁺ influx and reduction of intracellular terminal button Ca²⁺ ion concentration.

Transmission of action potentials from nerves to skeletal muscle fibers: The neuromuscular junction:

When the action potential arrives at the nerve terminal, this opens many voltage-gated Ca²⁺ channels at the wall of nerve terminal, resulting in influx of calcium ions from ECF to ICF of the nerve terminal.
As a result, the Ca²⁺ ion concentration in the terminal increase, which in turn increases the rate of fusion of the Ach-containing vesicles with the terminal membrane.
As each vesicle fuses, its outer surface ruptures through the cell membrane, thus causing exocytosis of Ach into the synaptic cleft.
Within about 1 msec after Ach is released by the axon terminal, much of it has already diffused out of the synaptic gutter and no longer acts on the muscle fiber membrane, and all the remaining is destroyed by the acetylcholinestrase in the basal lamina lying between the nerve terminal and the subneural clefts. However, the very short period of time that Ach remains in contact with the muscle fiber membrane is almost always sufficient to excite the muscle fiber. The rapid removal of the Ach prevents re-excitation after the muscle fiber has recovered from the first action potential.
During this very short time of Ach release, it interacts with nicotinic Ach-gated ion channels. The interaction of Ach with the receptors causes conformational changes in these transmembrane channel proteins that lead to open the Ach-gated channels. These channels allow Na⁺ and K⁺ ions to flow though the channels. Consequently, the postsynaptic membrane potential is depolarized to a value halfway between the Na⁺ and K⁺equilibrium potential. This means that the membrane potential in the local area of the muscle fiber to increase in the positive direction, creating a local depolarizing potentials called the end-plate potential. This local change in membrane potential is graded potentials.
If the summation of many end-plate potentials is sufficient enough, it may activate voltage-gated Na⁺ channel. Consequently, propagated action potential will occur.

Mechanism of muscle contraction (sliding filaments or walk along theory):

Each skeletal muscle fiber is excited by one of the terminal of large nerve fiber which attach to the middle of skeletal muscle fiber at the neuromuscular junction. There is only one neuromuscular junction to each muscle fiber locates near the middle of the fiber. Muscle contraction occurs through the following sequence:

The action potential is transmitted from the nerve fiber to its nerve terminals and then across the neuromuscular junction to the surface of skeletal muscle fiber.
The T- tubules of skeletal muscle fiber then transmit the surface action potential deep inside the muscle fiber.
This action potential in the T- tubules causes an activation of voltage sensors (DHP receptors) in the wall of T tubule.
Activation of DHP receptors lead to opening of Ca²⁺ channel (ryanodine Ca²⁺- channel) in the cisternae leading to rapid release of Ca²⁺ ions from the cisternae to the ICF of the muscle fibers.
The released Ca²⁺ to the ICF of the muscle fibers, then diffuse to the adjacent actin myofibrils where they bind strongly with troponin.
This Ca²⁺- troponin binding leads to move tropomyosin molecules away from the F-actin protein and consequently leads to exposure of the active sites (ADP). This is followed by interaction between actin protein active site and the cross-bridge of myosin (heads of myosin molecules). This interaction causes contraction to occur according to walk-along theory (or sliding filament theory) by sliding of thin filaments over the thick filaments. The sliding during muscle contraction in produced, according to walk-along theory by breaking and reforming of linkages between the cross-bridges of myosin and the actin active sites. It is postulated that when the head attached to actin, this attachment causes changes in the intermolecular forces in the head of the cross-bridge allowing the heads to be able to tilt and drags the actin filament along with it. The energy that activates this tilt is derived from cleavage of ATP that is bind to the head by the ATPase activity of the head of the cross-bridges (ATP > ADP ⁺ Pi⁺ E). Then, immediately after tilting, the head binds with a new ATP molecule which causing the head to break away from active site and return to its normal position. In this position it combines with a new active site farther down along the actin filament, and then a similar tilt takes place again.

The source of energy for the muscle: ATP supplies the energy required by the muscle. At rest and during light exercise, muscles utilize free fatty acids as their energy source to supply ATP. As the intensity of exercise increases, lipids alone cannot supply energy fast enough and so carbohydrates becomes the predominant component in the muscle fuel mixture. Fortunately, after the ATP is broken into ADP, the ADP is rephosphorylated to form new ATP within a fraction of sec. There are several sources of the energy for this rephosphorylation and these are:

The energy released from cleavage of phosphocreatine.
The energy released from the breakdown of glucose and glycogen to CO₂ and H₂O by the process of aerobic glycolysis (long time process, requires adequate blood circulation, provides large amount of ATP).
The energy released from the breakdown of glucose and glycogen to CO₂ and H₂O by the process of anaerobic glycolysis (short time process, doesn’t require adequate blood circulation, provides small amount of ATP).

The motor unit: It is the combination of the motor nerve cell (neuron) and all the muscle cells it innervates. It is of two types:

Slow motor unit: In which several hundred muscle fibers in a motor unit are present. This motor unit is seen in large muscles that react slowly and do not require a very fine degree of control.
Fast motor unit: In which few muscle fibers in a motor unit are present. This motor unit is seen in small muscles that react rapidly and require a very fine degree of control.

Types of muscle contraction: Muscle contraction is said to be isometric when the muscle does not shorten during contraction and isotonic when it shortens with a constant tension on the muscle. There are several basic differences between isometric and isotonic contraction:

Isometric contraction does not require much sliding of myofibrils among each other.
Isometric contraction requires a smaller amount of energy used by the muscle.
Isometric contraction does not do work. Most contractions of the muscle in the body are actually a mixture of the two.

Muscle fatigue: Muscle fatigue is the progressive weakness and loss of contractility that results from prolonged use of the muscles. Fatigue has multiple causes:

ATP synthesis declines as glycogen is consumed due to interruption of blood flow through a contracting muscle and the loss of nutrient supply. This will results in slow down the mechanism of muscle contraction and the sodium-potassium pumps (which are needed to maintain the resting membrane potential and excitability of the muscle fibers).
Accumulation of lactic acid lowers the pH of the sarcoplasm, which inhibits the enzymes involved in contraction, ATP synthesis, and other aspects of muscle function.
Motor nerve fibers use up their acetylcholine, which leaves them less capable of stimulating muscle fibers. This is called junctional fatigue.

Relationship between muscle length and tension: The length of the muscle at which the active tension is maximal is usually at its resting length (when the muscle attached to the bones). Increase or decrease the muscle length from its resting length will leads reduction in its tension. At a sarcomere length of 2.2 μm, overlap between thick and thin filaments is optimal and force development is maximal. Skeletal muscles operate at the plateau of their length-tension relationship curve.

By contrast, preload (initial muscle length) is not ﬁxed in cardiac muscle but varies according to the amount of venous return. Prior to filling with blood during diastole, the sarcomere lengths of myocardial cells are only about 1.5 μm and is at the ascending limb of muscle length-tension relationship curve. As the ventricles fill with blood, the myocardium stretches and operates at the plateau part of muscle length-tension relationship due to the increase in the number of interactions between actin and myosin, allowing more force to be developed during contraction. This phenomenon is called the Frank–Starling law. Cardiac muscle, unlike skeletal muscle, does not display a descending limb on the active tension curved because the greater stiffness of cardiac muscle normally prevents its sarcomeres from being stretched beyond 2.2 microns.

The length-tension relationship of smooth muscle is very different. The ability of the smooth muscle cell to generate active tension remains normal over a very wide range of changes in length. Smooth muscle can do this because it has no striations and the thick and thin filaments are not lined up in the rigid way that we see in skeletal muscle.

Types of muscle fibers: Depending upon contraction time and myosin ATPase activity the muscle fibers are divided into two types:
1. Type I fibers or slow fibers or slow twitch fibers, which have small diameter, designed for sustained contraction .
2. Type II fibers or fast fibers or fast twitch fibers, which have large diameter, designed for short contraction.
Most of the skeletal muscles in human beings contain both the types of fibers.

Types of muscles: Based on contraction time, the skeletal muscles are classified into two types:

Red muscles
Pale (white) muscles.

The smooth muscles: Smooth muscle can generally be divided into two major types, the multi-unit and the single unit smooth muscle.

Initiation of smooth muscle contraction and relaxation: Smooth muscles can contract or relax as a consequence of the increase or decrease the intracellular Ca²⁺ concentration. This is achieved by the following factors:

[1]. Action potential-smooth muscle contraction: As a result of the rhythmicity, Stretching the smooth muscles, or generation of Excitatory junctional potential (EJP), Depolarization of the plasma membrane of smooth muscle fiber can occur which leads to open of the membrane voltage-gated Ca²⁺ channels. Calcium ions diffuse through the Ca²⁺ channels from ECF to ICF.

[2]. Non action potential-smooth muscle contraction: Smooth muscle contraction can be initiated without the generation of an action potential as a result of local tissue factors or humeral factors. Humeral factors mechanism is the result of interaction between hormones, chemical agents or any other factors (norepinephrine, epinephrine, acetylcholine, angiotensin, vasopressin, oxytocin, serotonin, and histamine) with excitatory receptors of G protein at the surface of smooth muscle fibers. Humeral factors can increase intracellular Ca²⁺ concentration through activation of G protein, which in turn activates:

G protein-gated Ca²⁺ channels at the smooth muscle cell membrane or
Membrane phospholipase C → Release of IP3 → Activates IP3-gated Ca²⁺ channels at the membrane of endoplasmic reticulum → Ca²⁺ release from endoplasmic reticulum to cytosol.

However, the smooth muscles of the arterioles, metarterioles, and precapillary sphincters have little or no nervous supply. Yet, the smooth muscle is highly contractile, responding rapidly to change in local condition in the surrounding interstitial fluid (local tissue factors). Some of the specific control factors are: ↓oxygen, ↓Ca⁺⁺, ↓body temperature, ↑CO₂, ↑[H⁺], ↑Lactic acid, ↑[K⁺], ↑adenosine & phosphate compounds, in the local tissues all cause smooth muscle relaxation and therefore è vasodilatation. The mechanisms by which the local tissue factors excite or inhibit the smooth contraction not clear. It is possible that these factors cause change in the cell membrane potential, changes in the permeability of the membrane to Ca²⁺ ions, and/or changes in the intracellular contractile process.

Mechanism of smooth muscle excitation: As the ICF Ca²⁺ concentration increases, it binds with a regulatory protein called calmodulin (instead of troponin that present in skeletal muscle). This calmodulin-Ca²⁺ complex activate a phosphorylating enzyme called myosin light chain kinase (MLCK), which leads to phosphorylation of myosin head. This phosphorylation of the head of the cross-bridge will bring about the interaction between the head of myosin with the actin filament and preceding the same as occurs for skeletal muscle, thus causing muscle contraction. When the Ca²⁺ ion concentration falls below a critical level, all aforementioned processes reverse and the presence of an enzyme myosin phosphatase is required to dephosphorylate the head of the cross-bridge and consequently disengagement of the head from the actin filament (relaxation). However, myosin dephosphorylation does not necessarily lead to immediate smooth muscle relaxation due to the presence of latch bridge mechanism by which the dephosphorylated myosin cross-bridges remain attached to actin for some time after the cytoplasmic Ca²⁺ ion concentration falls. This produce sustained contraction with little expenditure of energy.

The main physiological differences of cardiac muscle fiber from that of skeletal muscle fiber:

The action potentials of the non-pacemaker cardiac muscle fibers (atria, ventricles and Purkinje fibers) characterized by the presence of plateau.
The duration of cardiac action potential is much longer.
In cardiac pacemaker cells (sinoatrial and atrio-venticular nodes), calcium ions (through voltage-gated Ca²⁺ channels) are responsible of depolarization phase of the action potential rather than voltage-gated Na⁺ channels.
The cardiac muscle is absolutely refractory during most of the action potential (i.e. the duration of absolute refractory period is longer than in skeletal or nerve fiber). Therefore, tetanization of the type seen in skeletal muscle cannot occur. An electrical stimulus can sometimes initiate a new spike at the very end of the action potential, i.e. at the relative refractory period.