Cyclic GMP transporters.

The biokinetics of guanosine 3',5'-cyclic monophosphate (cGMP) is characterized by three distinct processes: synthesis by guanylate cyclases (GCs), conversion of cGMP to GMP by cyclic nucleotide phosphodiesterases (PDEs) and the excretion of unchanged cGMP by transport proteins in the cell membrane. Efflux is observed in virtually all cell types including cells which originate from brain. Studies of intact cells, in which metabolic inhibitors and probenecid reduced extrusion of cGMP and wherein cGMP was extruded against concentration gradients, indicated the existence of ATP requiring organic anion transport system(s). Functional studies of inside-out vesicles have revealed cGMP transport systems wherein translocation is coupled to hydrolysis of ATP. The extrusion of cGMP is inhibited by a number of unrelated compounds and this indicates that cGMP is substrate for multispecific transporters. Recent transfection studies suggest that members of the MRP (multidrug resistance protein) family; MRP4, MRP5 and MRP8 translocate cGMP across the cell membrane. Many of the MRPs have been detected in brain. In addition tertiary active transport by the organic anion transporter family has also been identified. At least one member (OAT1) shows relative high affinity for cGMP and is also expressed in brain. The biological significance of cGMP transporters has to be clarified. Their role in cGMP biokinetics, being responsible for one of the cellular elimination pathways, is well established. However, there is growing evidence that extracellular cGMP has effects on cell physiology and pathophysiology by an auto- or paracrine mechanism.