Functional Significance of Cell Volume Regulatory Mechanisms
Functional Significance of Cell Volume Regulatory Mechanisms
Functional Significance of Cell Volume Regulatory Mechanisms
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264<br />
G. Others<br />
In addition to hormones, a great number <strong>of</strong> drugs and<br />
toxins lead to cell swelling or cell shrinkage (Table 2).<br />
For most substances, the functional significance <strong>of</strong> the<br />
effect on cell volume has not been explored.<br />
In several stress situations, such as surgical intervention<br />
(306), acute pancreatitis (1027), severe injury, burns,<br />
and sepsis (79), a decrease <strong>of</strong> muscle intracellular space<br />
has been observed, leading to disinhibition <strong>of</strong> proteolysis<br />
and thus to hypercatabolism (507). However, the mechanisms<br />
underlying muscle cell shrinkage have not yet been<br />
elucidated.<br />
V. ROLE OF CELL VOLUME REGULATORY<br />
MECHANISMS IN CELL FUNCTIONS<br />
A. Erythrocyte Function<br />
Erythrocyte volume and shape are important determinants<br />
<strong>of</strong> blood viscosity. <strong>Cell</strong> volume regulatory mechanisms<br />
are specifically important in limiting alterations <strong>of</strong><br />
cell volume during their passage through the hypertonic<br />
kidney medulla and during HCO 0 3 transport in the lung<br />
and the periphery. One disorder exacerbated by altered<br />
LANG ET AL. <strong>Volume</strong> 78<br />
erythrocyte cell volume regulatory mechanisms is sickle<br />
cell anemia, where mutations <strong>of</strong> the hemoglobin chain<br />
FIG. 1. Three examples illustrating role <strong>of</strong> cell volume in coupling<br />
<strong>of</strong> apical to basolateral cell membranes in epithelia. A: Na / (HbS) favor the polymerization <strong>of</strong> deoxygenated hemoglo-<br />
-coupled<br />
transport across apical cell membrane <strong>of</strong> proximal renal tubules leads<br />
to accumulation <strong>of</strong> Na / bin, leading to characteristic changes <strong>of</strong> cell shape (sick-<br />
and substrate [e.g., amino acids (AA)] and thus<br />
to cell swelling, which activates basolateral K / ling) and impaired deformability <strong>of</strong> the erythrocytes (591,<br />
channels. B: electrolyte<br />
uptake by Na / -K / -2Cl 0 737); the consequence is a severe increase <strong>of</strong> blood viscoscotransport<br />
across basolateral cell membrane in<br />
dark vestibular cells leads to cell swelling and subsequent activation <strong>of</strong><br />
luminal K / channels. C: stimulation <strong>of</strong> apical Cl 0 channels in Cl 0 ity (591). The polymerization <strong>of</strong> hemoglobin is highly de-secreting<br />
cells leads to loss <strong>of</strong> Cl 0 and, because <strong>of</strong> depolarization, <strong>of</strong> K / pendent on protein concentration and thus on cell volume<br />
. <strong>Cell</strong><br />
shrinkage and decrease <strong>of</strong> intracellular Cl 0 activity in turn stimulate<br />
(297, 298). In HbS erythrocytes, volume regulatory KCl basolateral Na / -K / -2Cl 0 cotransport.<br />
cotransport (133, 163, 164, 343, 1276) is enhanced, partially<br />
due to direct interaction with the mutated hemoglo-<br />
bin (914). Furthermore, cell shrinkage is presumably fa-<br />
vored by enhanced activity <strong>of</strong> Ca 2/ -sensitive K / channels<br />
(105, 134, 343) due to increase <strong>of</strong> intracellular Ca 2/ con-<br />
centration. The ensuing cell shrinkage further favors the<br />
polymerization <strong>of</strong> hemoglobin (591). The expression <strong>of</strong><br />
the Na / /H / exchanger is enhanced, possibly in compensa-<br />
tion for cell shrinkage (165). Similarly, cell volume is decreased<br />
in homozygous hemoglobin C disease (135).<br />
B. Epithelial Transport<br />
Transcellular ion transport in epithelia is accom-<br />
plished by entry mechanisms across one cell membrane<br />
and ion exit mechanisms at the other cell membrane. Obviously,<br />
the entry or extrusion <strong>of</strong> osmotically active sub-<br />
stances during epithelial transport represents a continu-<br />
In intestine, gallbladder, and renal proximal tubules<br />
(see Fig. 1A), the luminal uptake <strong>of</strong> substrates for Na / -<br />
coupled transport, such as glucose or amino acids, tends<br />
to swell the cells, leading to volume regulatory activation<br />
<strong>of</strong> K / channels in the basolateral cell membrane (67, 68,<br />
122, 173, 355, 493, 687, 692, 706, 782, 995, 1092–1096,<br />
1230). The activation <strong>of</strong> these channels not only limits<br />
cell swelling but maintains the electrical driving force for<br />
continued transport.<br />
In the NaCl-reabsorbing thick ascending limb <strong>of</strong><br />
Henle’s loop and diluting segment <strong>of</strong> the amphibian kid-<br />
ney, NaCl entry is accomplished by luminal Na / -K / -2Cl 0<br />
cotransport, basolateral Cl 0 channels, and Na / -K / -<br />
ATPase as well as apical and basolateral K / channels (416,<br />
900, 1178). Inhibition <strong>of</strong> Na / -K / -ATPase leads to rapid cell<br />
swelling, which is prevented by inhibition <strong>of</strong> luminal Na / -<br />
ous challenge to cell volume constancy. K / -2Cl 0 cotransport (444, 520, 1178). On the other hand,<br />
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