Summary

Hypoxic pulmonary vasoconstriction involves a rise in [Ca2+], in PASMCs, brought about by the release of Ca2+from intracellular stores in the SR and Ca2+ influx through voltage-gated and voltage-independent channels.

Protein Dag Ip3 Trpc

Figure 3. Simplified model depicting the relationship between G-protein coupled receptors (GPCR), SR Ca2+ stores and voltage-independent Ca entry in pulmonary artery myocytes. Agonist binding to its GPCR causes it to interact with the G^n protein, thereby stimulating PLC activity to generate DAG and IP3 from PIP2. DAG directly activates Ca2+ influx through nonselective ROCs, formed by TRPC6 proteins and possibly TRPC3, also found in these cells. IP3 stimulates Ca2+ release from the SR via IP3-gated Ca2+ channels to promote store depletion which, by an unknown mechanism, activates SOCs formed by TRPC1 (possibly co-assembled with TRPC4 or TRPC5). Hypoxia activates SOC activity and CCE by an unknown mechanism that could involve the elevation of p-NADH levels, enhanced synthesis of cADPR and SR Ca2+ release via ryanodine receptor-channels.

Figure 3. Simplified model depicting the relationship between G-protein coupled receptors (GPCR), SR Ca2+ stores and voltage-independent Ca entry in pulmonary artery myocytes. Agonist binding to its GPCR causes it to interact with the G^n protein, thereby stimulating PLC activity to generate DAG and IP3 from PIP2. DAG directly activates Ca2+ influx through nonselective ROCs, formed by TRPC6 proteins and possibly TRPC3, also found in these cells. IP3 stimulates Ca2+ release from the SR via IP3-gated Ca2+ channels to promote store depletion which, by an unknown mechanism, activates SOCs formed by TRPC1 (possibly co-assembled with TRPC4 or TRPC5). Hypoxia activates SOC activity and CCE by an unknown mechanism that could involve the elevation of p-NADH levels, enhanced synthesis of cADPR and SR Ca2+ release via ryanodine receptor-channels.

As summarized in Figure 3, there is a close relationship between the SR and Ca2+ entry pathways. Thus, in the presence of the pre-tone which is often required to study HPV, agonists acting via the Gq/1, protein would mobilize Ca2+ from the SR via IP3 receptors and Ca2+ entry via ROCs. TRPC6 subunits are thought to form the ROC, possibly in a complex with other TRPC proteins. Hypoxia has a synergistic action, stimulating Ca2+ release from the SR via ryanodine receptor channels. The mechanism responsible for this effect is not yet known, but it may be mediated by the ryanodine receptor agonist cADPR. There is evidence that CCE is also stimulated by hypoxia and that this may provide the [Ca2+]; needed to sustain the hypoxic contraction. This could be a direct effect of hypoxia, or it could result from excessive depletion of the SR Ca2+ store, brought about by the combined effect of agonist and hypoxia, causing Ca2+ release via synergistic pathways. Store depletion activates non-selective cation channels that are distinct from ROCs. These SOCs are probably composed of TRPC1 subunits, either as a homologous channel or in a heteromeric complex with TRPC4 or TRPC5. Since SOCs are permeable to Na+ as well as Ca2+, they could contribute to membrane depolarization, which would promote further Ca2+ entry via voltage-gated Ca2+ channels. Our knowledge of the roles of TRPC channels and CCE in hypoxic pulmonary vasoconstriction is still preliminary, but rapid progress is being made and we can look forward to gaining a better understanding of their involvement very soon.

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