Regulation of Intracellular [Ca2 in PASMC

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The lipid membrane is impermeable to cations (e.g., K+, Ca2+) and anions (e.g., CI"). Flux of ions across either the plasma membrane or the intraorganelle membrane requires ion channels which selectively allow various ions to go through based on their concentration gradients. Furthermore, ions can be transported across the plasma membrane and the intraorganelle membrane against their concentration gradients by ion pumps (or ion transporters) (10).

The concentration of extracellular or intercellular is in the range of 1.6-2.0 mM (similar to the concentration in the plasma), while the concentration of cytoplasmic Ca2+ in an unstimulated cell is -100 nM. The concentration of Ca2+ in the SR ([Ca2+]SR) has been demonstrated in the range of 0.1-1.0 mM (10). Therefore, the Ca2+ concentration gradient across the plasma membrane favors Ca2+ entry to the cytoplasm, while the Ca2+ concentration gradient across the SR membrane favors Ca2+ mobilization from the SR to the cytoplasm (Fig. 2A). The passive Ca2+ influx (from the extracellular milieu) and release (from the SR) to the cytoplasm are driven by the electrochemical gradient that causes [Ca2+]cyt to rise without expenditure of energy.

In vascular smooth muscle cells, [Ca2+]cyt can be increased by a) Ca2+ release from intracellular stores (mainly the SR) to the cytosol through Ca2+-permeable channels, such as inositol 1,4,5-trisphosphate (IP3) and ryanodine receptor-coupled Ca2+ release channels, in the SR membrane and b) Ca2+ influx from extracellular/intercellular site to the cytosol through Ca2+-permeable channels in the plasma membrane (Fig. 2B). Increased [Ca2+]cyt can be reduced to the resting level by Ca2+ extrusion from the cytoplasm to extracellular/ intercellular site via the Ca2+-Mg2+ATPase and Na+/Ca2+exchange in the plasma membrane and Ca2+ sequestration from the cytoplasm into the SR via the Ca2+-Mg2+ ATPase in the SR membrane (SERCA) (Fig. 2B).

Figure 2. Schematic diagrams showing Ca2+ distribution and ion channels involved in regulating [Ca2+]cyt. A: Ca2t is more concentrated in the extracellular milieu and in the sarcoplasmic reticulum (SR) than in the cytosol. B: Key ion channels involved in the regulation of [Ca2+]„, include the plasma membrane voltage-dependent Ca2t channels (VDCC), store-operated Ca channels (SOC), and receptor-operated Ca channels (ROC). Energy-driven transporters such as the Ca2+-ATPase and the Na+-Ca2+ exchanger are primarily responsible for Ca2+ extrusion from the cytosol. On the SR membrane, ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP3) receptors act as Ca2+ release pathways from the SR while a Ca2+-ATPase pump is responsible for Ca2+ re-uptake and replenishing of SR Ca2+ stores.

In vascular smooth muscle cells, the SR has been demonstrated as the dominant intracellular Ca2+ store (9). There are two functionally and spatially distinguishable SR: a) an IP3-sensitive SR that is involved in Ca2+ mobilization during agonist stimulation and is sensitive to the SR Ca2+ pump inhibitors, cyclopiazonic acid (CPA) and thapsigargin (27); and b) a ryanodine-sensitive SR that is activated by caffeine and is responsible for Ca2+-induced Ca2+ release (10). Both IP3- and ryanodine-sensitive SR functionally exist in PASMC.

In pulmonary vascular smooth muscle cells, there are at least three functionally-distinct channels expressed in the plasma membrane

(Fig. 2B): a) voltage-dependent Ca2+ channels (DCC) that are opened by membrane depolarization (60), b) receptor-operated Ca2+ channels (ROC) that are opened by ligand binding with receptors (2); and c) store-operated Ca2+ channels (SOC) that are opened by depletion of Ca2+ from the intracellular Ca2+ stores (i.e., the SR) (67). By governing Ca2+influx via VDCC, membrane potential (Em) plays a critical role in regulating [Ca2+]cyt (60) and excitation-contraction coupling in smooth muscle (96), as well as in regulating cell proliferation (78).

Ca2 Proliferation

Figure 2. Schematic diagrams showing Ca2+ distribution and ion channels involved in regulating [Ca2+]cyt. A: Ca2t is more concentrated in the extracellular milieu and in the sarcoplasmic reticulum (SR) than in the cytosol. B: Key ion channels involved in the regulation of [Ca2+]„, include the plasma membrane voltage-dependent Ca2t channels (VDCC), store-operated Ca channels (SOC), and receptor-operated Ca channels (ROC). Energy-driven transporters such as the Ca2+-ATPase and the Na+-Ca2+ exchanger are primarily responsible for Ca2+ extrusion from the cytosol. On the SR membrane, ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP3) receptors act as Ca2+ release pathways from the SR while a Ca2+-ATPase pump is responsible for Ca2+ re-uptake and replenishing of SR Ca2+ stores.

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