Regulation of cAMP by phosphodiesterases in erythrocytes

Abstract

The erythrocyte, a cell responsible for carrying and delivering oxygen in the body, has often been regarded as simply a vehicle for the circulation of hemoglobin. However, it has become evident that this cell also participates in the regulation of vascular caliber in the microcirculation via release of the potent vasodilator, adenosine triphosphate (ATP). The regulated release of ATP from erythrocytes occurs via a defined signaling pathway and requires increases in cyclic 3',5'- adenosine monophosphate (cAMP). It is well recognized that cAMP is a critical second messenger in diverse signaling pathways. In all cells increases in cAMP are localized and regulated by the activity of phosphodiesterases (PDEs). In erythrocytes activation of either beta adrenergic receptors (beta(2)AR) or the prostacyclin receptor (IPR) results in increases in cAMP and ATP release. Receptor-mediated increases in cAMP are tightly regulated by distinct PDEs associated with each signaling pathway as shown by the finding that selective inhibitors of the PDEs localized to each pathway potentiate both increases in cAMP and ATP release. Here we review the profile of PDEs identified in erythrocytes, their association with specific signaling pathways and their role in the regulation of ATP release from these cells. Understanding the contribution of PDEs to the control of ATP release from erythrocytes identifies this cell as a potential target for the development of drugs for the treatment of vascular disease.

Figure 1

Activation of the β ₂AR with isoproterenol increases cAMP which then activates PKA. PKA then phosphorylates and activates CFTR which controls the activity of an ATP conduit in the erythrocyte membrane. Increases in cAMP associated with activation of the β ₂AR are regulated by the activities of both PDE2 and PDE4. Similarly, activation of the IPR by iloprost results in increases in cAMP which activate ATP release from the erythrocyte. However, in the case of the IPR signaling pathway, increases in cAMP are regulated by the activity of PDE3. Abbreviations: β ₂AR = β ₂ adrenergic receptor; Gs = the heterotrimeric G protein, Gs; α, β and γ = G protein subunits, PDE = phosphodiesterase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate, AMP = adenosine monophosphate; AC = adenylyl cyclase; PKA = protein kinase A; CFTR = cystic fibrosis transmembrane conductance regulator; ? = unknown ATP conduit; + = activation; IPR = prostacyclin receptor.

Figure 2

Stimulation of either the β ₂AR or the IPR leads to ATP release from the erythrocyte. Once released the ATP can activate purinergic receptors on endothelial cells leading to the formation and release of EDHF, PGI₂ or NO all of which can induce relaxation in the smooth muscle cell. Abbreviations: β ₂AR = β ₂ adrenergic receptor; Gs = the heterotrimeric G protein, Gs; α, β and γ = G protein subunits, PDE = phosphodiesterase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate, AMP = adenosine monophosphate; AC = adenylyl cyclase; PKA = protein kinase A; CFTR = cystic fibrosis transmembrane conductance regulator; ? = unknown ATP conduit; IPR = prostacyclin receptor; EDHF = endothelium-derived hyperpolarizing factor; PGI₂ = prostacyclin; NO = nitric oxide; cGMP = cyclic guanosine monophosphate.