The sodium ion (Na+) is an essential mineral for our body because it regulates the osmolality of the extracellular fluid and plays a key role in many physiological processes, from the generation of nerve impulses to renal function.
Sodium is an essential component for the excitability properties of both nerve and muscle tissue
Synaptic transmission and the generation of the action potential are both dependent on the presence of N
Treatment of brain injury can contribute to, and complicate the diagnosis of, sodium disorders.
Synaptic transmission and the generation of the action potential are both dependent on the presence of N
Na+ is lost continuously through urine, feces, and sweat. Thus, to maintain proper bodily balance, we need to replace losses by the ingestion of food containing this cation.
In these mammals, the epithelial sodium channel (ENaC) works as low-salt receptor, a diuretic drug, which selectively blocks the channel at submicromolar concentrations
The epithelial sodium channel (ENaC) is a key membrane protein underlying absorption of Na+ in many epithelia, such as those found in kidney, colon, and lung
The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [2,4,6-7,13]. In these epithelia, Na+ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC. The Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [11]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [1]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [12]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [9,12].
In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [5]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [5]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on non-cilial cell-surface [5]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [13]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [13]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation, and cell migration [5,7].
Some authors found that indeed the presence of amiloride reduced the perceived saltiness of the NaCl solutions,
application of NaCl solution to the tongue mucosa produces a transepithelial current due to the movement of ions across the epithelium [9,34,35]. This current is believed to be sustained mainly by Na+ entering taste cells via the apical ENaC since amiloride strongly reduces it.
amiloride (100 μM) was able to reduce the voltage drop caused by NaCl application
Amiloride is a potassium-sparing diuretic (water pill) that prevents your body from absorbing too much salt and keeps your potassium levels from getting too low. Amiloride is used to treat or prevent hypokalemia (low potassium levels in the blood) in people with high blood pressure or congestive heart failure.
The study of ENaC is tightly linked to the use of amiloride as pharmacological tool [43] . Amiloride affects several membrane transporters and ion channels; in the submicromolar concentration range, however, it is a specific reversible blocker of ENaC
Primary active transport
1. Characteristics of primary active transport
■ is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition. 2. Examples of primary active transport a. Na+,K+-ATPase (or Na+–K+ pump) in cell membranes transports Na+ from intracellular to extracellular fluid and K+ from extracellular to intracellular fluid; it maintains low intracellular [Na+] and high intracellular [K+].
■ Both Na+ and K+ are transported against their electrochemical gradients.
■ The usual stoichiometry is 3 Na+/2 K+
. ■ Specific inhibitors of Na+,K+-ATPase are the cardiac glycoside drugs ouabain and digitalis. b. Ca2+-ATPase (or Ca2+ pump) in the sarcoplasmic reticulum (SR) or cell membranes transports Ca2+ against an electrochemical gradient.
■ Sarcoplasmic and endoplasmic reticulum Ca2+-ATPase is called SERCA. c. H+,K+-ATPase (or proton pump) in gastric parietal cells transports H+ into the lumen of the stomach against its electrochemical gradient.
■ It is inhibited by proton pump inhibitors, such as omeprazole. E. Secondary active transport 1. Characteristics of secondary active transport a. The transport of two or more solutes is coupled. b. One of the solutes (usually Na+) is transported “downhill” and provides energy for the “uphill” transport of the other solute(s). c. Metabolic energy is not provided directly, but indirectly from the Na+ gradient that is maintained across cell membranes. Thus, inhibition of Na+,K+-ATPase will decrease transport of Na+ out of the cell, decrease the transmembrane Na+ gradient, and eventually inhibit secondary active transport. d. If the solutes move in the same direction across the cell membrane, it is called cotransport, or symport.
■ Examples are Na+–glucose cotransport in the small intestine and Na+–K+–2Cl– cotransport in the renal thick ascending limb. e. If the solutes move in opposite directions across the cell membranes, it is called counter - transport, exchange, or antiport.
■ Examples are Na+–Ca2+ exchange and Na+–H+ exchange.
2. Example of Na+–glucose cotransport (Figure 1-1) a. The carrier for Na+–glucose cotransport is located in the luminal membrane of intestinal mucosal and renal proximal tubule cells. b. Glucose is transported “uphill”; Na+ is transported “downhill.” c. Energy is derived from the “downhill” movement of Na+. The inwardly directed Na+ gradient is maintained by the Na+–K+ pump on the basolateral (blood side) membrane. Poisoning the Na+–K+ pump decreases the transmembrane Na+ gradient and consequently inhibits Na+–glucose cotransport.
3. Example of Na+–Ca2+ countertransport or exchange (Figure 1-2) a. Many cell membranes contain a Na+–Ca2+ exchanger that transports Ca2+ “uphill” from low intracellular [Ca2+] to high extracellular [Ca2+]. Ca2+ and Na+ move in opposite directions across the cell membrane. b. The energy is derived from the “downhill” movement of Na+. As with cotransport, the inwardly directed Na+ gradient is maintained by the Na+–K+ pump. Poisoning the Na+–K+ pump therefore inhibits Na+–Ca2+ exchange.
Inorganic materials are as much an integral component of protoplasm as proteins, carbohydrates, and lipids; without them physiologic processes are impossible. Among the inorganic
constituents of protoplasm are calcium, potassium, sodium, and magnesium present as carbonates, chlorides, phosphates, and sulfates; small quantities of iron, copper, and iodine; and trace elements such as cobalt, manganese, zinc, and other metals. The inorganic materials have many functions, including maintenance of intracellular and extracellular osmotic pressures, transmission of nerve impulses, contraction of muscle, adhesiveness of cells, activation of enzymes, transport of oxygen, and maintenance of the rigidity of tissues such as bone.
The plasmalemma of these regions is rich in ion channel proteins, in particular sodiumpotassium-ATPase.
The plasmalemma of the ruffled border is rich in sodium/potassium ATPase and carbonic anhydrase that produces hydrogen ions
The extracellular fluid contains large
amounts of sodium, chloride, and bicarbonate ions plus
nutrients for the cells, such as oxygen, glucose, fatty acids,
and amino acids. It also contains carbon dioxide
The intracellular fluid differs significantly from the
extracellular fluid; for example, it contains large amounts
of potassium, magnesium, and phosphate ions instead of
the sodium and chloride ions found in the extracellular
fluid.
Hormones are transported in the extracellular
fluid to all parts of the body to help regulate cellular
function. For instance, thyroid hormone increases
the rates of most chemical reactions in all cells, thus helping
to set the tempo of bodily activity. Insulin controls
glucose metabolism; adrenocortical hormones control
sodium ion, potassium ion, and protein metabolism; and
parathyroid hormone controls bone calcium and phosphate.
The liver and pancreas regulate
the concentration of glucose in the extracellular fluid,
and the kidneys regulate concentrations of hydrogen,
sodium, potassium, phosphate, and other ions in the
extracellular fluid.
In addition to membrane transport of sodium, energy
from ATP is required for membrane transport of potassium
ions, calcium ions, magnesium ions, phosphate ions chloride ions, urate ions, hydrogen ions, and many other
ions and various organic substances.
Potassium channels permit passage of potassium ions
across the cell membrane about 1000 times more readily
than they permit passage of sodium ions. This high degree
of selectivity, however, cannot be explained entirely by
molecular diameters of the ions since potassium ions
are slightly larger than sodium ions.
Electrical current flowing
through a single sodium channel when there was an
approximate 25-millivolt potential gradient across the
membrane.
Osmosis occurs
from the pure water into the sodium chloride solution.
pressure were applied to the sodium chloride
solution, osmosis of water into this solution would
be slowed, stopped, or even reversed. The exact amount
of pressure required to stop osmosis is called the osmotic
pressure of the sodium chloride solution.
Some energy source must cause excess movement
of potassium ions to the inside of cells and excess
movement of sodium ions to the outside of cells. When a
cell membrane moves molecules or ions “uphill” against a
concentration gradient (or “uphill” against an electrical or
pressure gradient), the process is called active transport.
Different substances that are actively transported
through at least some cell membranes include sodium
ions, potassium ions, calcium ions, iron ions, hydrogen
ions, chloride ions, iodide ions, urate ions, several
different sugars, and most of the amino acids.
Among the substances that are transported by primary
active transport are sodium, potassium, calcium,
hydrogen,
chloride, and a few other ions.
The active transport mechanism that has been studied
in greatest detail is the sodium-potassium (Na+-K+)
pump, a transport process that pumps sodium ions outward
through the cell membrane of all cells and at the
same time pumps potassium ions from the outside to
the inside. This pump is responsible for maintaining the
sodium and potassium concentration differences across
the cell membrane, as well as for establishing a negative
electrical voltage inside the cells. Indeed, Chapter 5 shows
that this pump is also the basis of nerve function, transmitting
nerve signals throughout the nervous system.
When two potassium ions bind on the outside of
the carrier protein and three sodium ions bind on the
inside, the ATPase function of the protein becomes activated.
As with other enzymes, the Na+-K+ ATPase pump can
run in reverse. If the electrochemical gradients for Na+ and
K+ are experimentally increased enough so that the energy
stored in their gradients is greater than the chemical energy
of ATP hydrolysis, these ions will move down their concentration
gradients and the Na+-K+ pump will synthesize ATP
from ADP and phosphate. The phosphorylated form of the
Na+-K+ pump, therefore, can either donate its phosphate to
ADP to produce ATP or use the energy to change its conformation
and pump Na+ out of the cell and K+ into the cell.
The relative concentrations of ATP, ADP, and phosphate, as
well as the electrochemical gradients for Na+ and K+, determine
the direction of the enzyme reaction. For some cells,
such as electrically active nerve cells, 60 to 70 percent of the
cells’ energy requirement may be devoted to pumping Na+
out of the cell and K+ into the cell.
The Na+-K+ Pump is Important For Controlling Cell
Volume. One of the most important functions of the
Na+-K+ pump is to control the volume of each cell.
Without function of this pump, most cells of the body
would swell until they burst. The mechanism for controlling
the volume is as follows: Inside the cell are large numbers
of proteins and other organic molecules that cannot
escape from the cell. Most of these are negatively charged
and therefore attract large numbers of potassium, sodium,
and other positive ions as well. All these molecules and
ions then cause osmosis of water to the interior of the
cell. Unless this is checked, the cell will swell indefinitely
until it bursts. The normal mechanism for preventing this
is the Na+-K+ pump. Note again that this device pumps
three Na+ ions to the outside of the cell for every two K+
ions pumped to the interior. Also, the membrane is far
less permeable to sodium ions than to potassium ions,
so once the sodium ions are on the outside, they have a
strong tendency to stay there. Thus, this represents a net
loss of ions out of the cell, which initiates osmosis of water
out of the cell as well.
If a cell begins to swell for any reason, this automatically
activates the Na+-K+ pump, moving still more ions
to the exterior and carrying water with them. Therefore,
the Na+-K+ pump performs a continual surveillance role
in maintaining normal cell volume.
Electrogenic Nature of the Na+-K+ Pump. The fact that
the Na+-K+ pump moves three Na+ ions to the exterior for
every two K+ ions to the interior means that a net of one
positive charge is moved from the interior of the cell to the
exterior for each cycle of the pump. This creates positivity outside the cell but leaves a deficit of positive ions inside the
cell; that is, it causes negativity on the inside. Therefore, the
Na+-K+ pump is said to be electrogenic because it creates an
electrical potential across the cell membrane. As discussed
in Chapter 5, this electrical potential is a basic requirement
in nerve and muscle fibers for transmitting nerve and muscle
signals.
When sodium ions are transported out of cells by primary
active transport, a large concentration gradient of
sodium ions across the cell membrane usually develops—
high concentration outside the cell and low concentration
inside. This gradient represents a storehouse of energy
because the excess sodium outside the cell membrane is
always attempting to diffuse to the interior. Under appropriate
conditions, this diffusion energy of sodium can pull
other substances along with the sodium through the cell
membrane. This phenomenon is called co-transport; it is
one form of secondary active transport
Co-Transport of Glucose and Amino Acids
Along with Sodium Ions
Glucose and many amino acids are transported into most
cells against large concentration gradients; the mechanism
of this is entirely by co-transport, as shown in Figure
4-13. Note that the transport carrier protein has two
binding sites on its exterior side, one for sodium and one for glucose. Also, the concentration of sodium ions is high
on the outside and low inside, which provides energy for
the transport. A special property of the transport protein
is that a conformational change to allow sodium movement
to the interior will not occur until a glucose molecule
also attaches. When they both become attached,
the conformational change takes place automatically, and
the sodium and glucose are transported to the inside of
the cell at the same time. Hence, this is a sodium-glucose
co-transport mechanism. Sodium-glucose co-transporters
are especially important mechanisms in transporting
glucose across renal and intestinal epithelial cells, as discussed
in Chapters 27 and 65.
molecular characteristics.
Sodium co-transport of glucose and amino acids
occurs especially through the epithelial cells of the intestinal
tract and the renal tubules of the kidneys to promote
absorption of these substances into the blood, as is discussed
in later chapters.
Two especially important counter-transport mechanisms
(transport in a direction opposite to the primary ion) are
sodium-calcium counter-transport and sodium-hydrogen
counter-transport.
Sodium-calcium counter-transport occurs through all
or almost all cell membranes, with sodium ions moving
to
the interior and calcium ions to the exterior, both bound
to the same transport protein in a counter-transport
mode. This is in addition to primary active transport of
calcium that occurs in some cells.
Sodium-hydrogen counter-transport occurs in several
tissues. An especially important example is in the proximal
tubules of the kidneys, where sodium ions move
from the lumen of the tubule to the interior of the tubular
cell, while hydrogen ions are counter-transported into
the tubule lumen. As a mechanism for concentrating
hydrogen ions, counter-transport is not nearly as powerful
as the primary active transport of hydrogen ions that
occurs in the more distal renal tubules, but it can transport
extremely large numbers of hydrogen ions, thus making
it a key to hydrogen ion control in the body fluids, as
discussed in detail in Chapter 30.
First, sodium, potassium, and chloride ions are
the most important ions involved in the development of
membrane potentials in nerve and muscle fibers, as well as
in the neuronal cells in the nervous system.
First, let us recall from Chapter 4 that
all cell membranes of the body have a powerful Na+-K+
pump that continually transports sodium ions to the outside
of the cell and potassium ions to the inside, as illustrated
on the left-hand side in Figure 5-4. Further, note
that this is an electrogenic pump because more positive
charges are pumped to the outside than to the inside
(three Na+ ions to the outside for each two K+ ions to the
inside), leaving a net deficit of positive ions on the inside;
this causes a negative potential inside the cell membrane.
The Na+-K+ pump also causes large concentration gradients
for sodium and potassium across the resting nerve
membrane.
addition of
slight permeability of the nerve membrane to sodium ions,
caused by the minute diffusion of sodium ions through
the K+-Na+ leak channels. The ratio of sodium ions from
inside to outside the membrane is 0.1, and this gives a calculated
Nernst potential for the inside of the membrane of
+61 millivolts.
Contribution of the Na+-K+ Pump. In Figure 5-5C,
the Na+-K+ pump is shown to provide an additional contribution
to the resting potential. In this figure, there is continuous
pumping of three sodium ions to the outside for
each two potassium ions pumped to the inside of the membrane.
The fact that more sodium ions are being pumped
to the outside than potassium to the inside causes continual
loss of positive charges from inside the membrane;
this creates an additional degree of negativity (about −4
millivolts additional) on the inside beyond that which can
be accounted for by diffusion alone. Therefore, as shown
in Figure 5-5C, the net membrane potential with all these
factors operative at the same time is about −90 millivolts.
When sodium is the only
permeant ion in the solutions inside and outside the squid
axon, the voltage clamp measures current flow only through
the sodium channels. When potassium is the only permeant
ion, current flow only through the potassium channels is
measured.
for the original establishment
of the resting potential. That is, sodium ions
that have diffused to the interior of the cell during the
action potentials and potassium ions that have diffused
to the exterior must be returned to their original state by
the Na+-K+ pump. Because this pump requires energy for
operation, this “recharging” of the nerve fiber is an active
metabolic process, using energy derived from the adenosine
triphosphate (ATP) energy system of the cell
Mechanisms of Smooth Muscle:
Some
hormone receptors in the smooth muscle membrane open
sodium or calcium ion channels and depolarize the membrane,
the same as after nerve stimulation.
Inhibition, in contrast, occurs when the hormone (or
other tissue factor) closes the sodium and calcium channels
to prevent entry of these positive ions; inhibition
also occurs if the normally closed potassium channels are
opened, allowing positive potassium ions to diffuse out of
the cell. Both of these actions increase the degree of negativity
inside the muscle cell, a state called hyperpolarization,
which strongly inhibits muscle contraction
In cardiac muscle, the action potential is caused by
opening of two types of channels: (1) the same fast sodium
channels as those in skeletal muscle and (2) another entirely
different population of slow calcium channels, which are
also called calcium-sodium channels. This second population
of channels differs from the fast sodium channels in
that they are slower to open and, even more important,
remain open for several tenths of a second. During this
time, a large quantity of both calcium and sodium ions
flows through these channels to the interior of the cardiac
muscle fiber, and this maintains a prolonged period
of depolarization, causing the plateau in the action potential.
Calcium ions are
also removed from the cell by a sodium-calcium exchanger.
The sodium that enters the cell during this exchange is
then transported out of the cell by the sodium-potassium
ATPase pump. As a result, the contraction ceases until
a new action potential comes along.
Therefore, between heartbeats,
influx of positively charged sodium ions causes a slow
rise in the resting membrane potential in the positive
direction.
Two general classes of drugs are used to treat hypertension:
(1) vasodilator drugs that increase renal blood
flow and (2) natriuretic or diuretic drugs that decrease
tubular reabsorption of salt and water.
Vasodilator drugs usually cause vasodilation in many
other tissues of the body, as well as in the kidneys. Different
ones act in one of the following ways: (1) by inhibiting
sympathetic nervous signals to the kidneys or by blocking
the action of the sympathetic transmitter substance
on the renal vasculature and renal tubules, (2) by directly
relaxing the smooth muscle of the renal vasculature, or
(3) by blocking the action of the renin-angiotensin system
on the renal vasculature or renal tubules.
Those drugs that reduce reabsorption of salt and
water by the renal tubules include especially drugs that
block active transport of sodium through the tubular
wall; this blockage in turn also prevents the reabsorption
of water, as explained earlier in the chapter. These natriuretic
or diuretic drugs are discussed in greater detail in
Chapter 31.
Active transport of sodium and potassium through
the cell membrane is greatly diminished. As a result,
sodium and chloride accumulate in the cells and potassium
is lost from the cells. In addition, the cells begin
to swell.
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