The rapid uptake of NaCl and various organic osmolytes is achieved through the regulatory volume increase response. This response involves the activation of the Na+-H+ antiporter (NHE-1), the 1Na+,1K+,2Cl− symporter (NKCC1), and several cation-selective channels, which work together to bring NaCl into the cell. The Na+,K+-ATPase then removes Na+ in exchange for K+, resulting in an increase in the KCl content of the cell. Additionally, several organic osmolyte transporters, such as the 3Na+,1Cl−-taurine symporter, 3Na+,2Cl−-betaine symporter, 2Na+–myo-inositol symporter, and Na+–amino acid symporter, are activated to further increase cell volume. These transporters utilize the Na+ and Cl− gradients to facilitate the secondary active uptake of organic osmolytes into cells.

On the other hand, the regulatory volume decrease response leads to the loss of KCl and organic osmolytes from the cell. This occurs through the activation of various K+selective, Cl−-selective, and anion-selective channels, as well as K+-Cl− symporters. The specific channels involved may vary depending on the cell type. Some organic osmolytes may leave the cell via anion channels, such as volume-sensitive organic osmolyte-anion channels.

Multiple mechanisms contribute to the activation of these transporters during the volume regulatory responses. The cytoskeleton, changes in macromolecular crowding and ionic strength of the cytoplasm, and stretch of the plasma membrane play roles in monitoring changes in cell volume. Additionally, stretch-activated cation channels, which can be directly or indirectly influenced by plasma membrane stretch, are involved. Various second messenger systems, including intracellular [Ca++], calmodulin, protein kinase A, and protein kinase C, may also participate in these responses, although the exact mechanisms remain incompletely defined.
The regulatory volume increase response results in the rapid uptake of NaCl and a number of organic osmolytes. To increase cell volume there is an activation of the Na+-H+ antiporter (NHE-1), the 1Na+,1K+,2Cl− symporter (NKCC1), and a number of cation-selective channels, which together bring NaCl into the cell. The Na+,K+-ATPase then extrudes the Na+ in exchange for K+ , so that ultimately the KCl content of the cell is increased. Several organic osmolyte transporters are also activated to increase cell volume. These include a 3Na+,1Cl−-taurine symporter, a 3Na+,2Cl−-betaine symporter, a 2Na+–myo-inositol symporter, and a Na+– amino acid symporter. These transporters use the energy in the Na+ and Cl− gradients to drive the secondary active uptake of these organic osmolytes into cells.
The regulatory volume decrease response results in the loss of KCl and organic osmolytes from the cell. The loss of KCl occurs through the activation of a wide range of K+selective, Cl−-selective, and anion-selective channels (the specific channels involved vary depending on the cell), as well as through activation of K+-Cl− symporters. Some of the organic osmolytes appear to leave the cell via anion channels (e.g., volume-sensitive organic osmolyte-anion channels).
Several mechanisms are involved in activation of these various transporters during the volume regulatory
CHAPTER 2 Homeostasis: Volume and Composition of Body Fluid Compartments 2Cl Na+, Cl– Na+ + •Fig. 2.7 Volume Regulation of Cells in Hypotonic and Hypertonic Media. Top, Whencellsareexposedtoahypotonicmedium,theyswellandthenundergoavolume-regulatorydecrease(RVD).TheRVDinvolveslossofKClandorganicosmolytesfromthecell.ThedecreaseincellularKClandorganicosmolytescausesintracellularosmoticpressuretodecrease,waterleavesthecell,andthecellreturnstonearlyitsoriginalvolume.Bottom, Whencellsareexposedtoahypertonicmedium,theyshrinkandthenundergoavolume-regulatoryincrease(RVI).DuringtheRVI,NaClandorganicosmolytesenterthecell.TheincreaseintheactivityofNa+,K+-ATPase(notdepicted)enhancestheexchangeNa+ forK+ sothattheK+ (andCl−)contentofthecellisincreased.TheincreaseincellularKCl,alongwithariseinintracellularorganicosmolytes,increasesintracellularosmoticpressure,whichbringswaterbackintothecell,andthecellvolumereturnstonearlyitsoriginalvolume.π,theoncoticpressureinsidethecell.
responses. Changes in cell volume appear to monitored by the cytoskeleton, by changes in macromolecular crowding and ionic strength of the cytoplasm, and by channels whose gating is influenced, either directly or indirectly, by stretch of the plasma membrane (e.g., stretch-activated cation channels). A number of second messenger systems may also be involved in these responses (e.g., intracellular [Ca++], calmodulin, protein kinase A, and protein kinase C), but the precise mechanisms have not been defined completely.
Principles of Epithelial Transport