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Prostacyclin receptor regulation--from transcription to trafficking.

ABSTRACT: The prostacyclin receptor (IP--International Union of Pharmacology nomenclature) is a member of the seven transmembrane G-protein coupled receptor (GPCR) superfamily. Recent concerns with selective and non-selective COX-1/COX-2 inhibition have exposed an important cardioprotective role for IP in preventing atherothrombosis. Receptor dysfunction (genetic variants) or reduced signaling (COX-2 inhibition) in high cardiovascular risk patients leads to increased cardiovascular events. These clinical observations have also been confirmed genetically by mouse knockout studies. Thus, receptor regulation is paramount in ensuring correct function in the prevention of atherothrombosis. This review summarizes recent literature on how this important receptor is regulated, from transcription to transport (to and from the membrane surface). These regulatory processes are critical in ensuring that IP receptors are adequately expressed and functional on the cell surface.

SUBMITTER: Midgett C

PROVIDER: S-EPMC3647249 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Prostacyclin receptor regulation--from transcription to trafficking.

Midgett C C Stitham J J Martin K A K Hwa J J

Current molecular medicine 20111001 7

The prostacyclin receptor (IP--International Union of Pharmacology nomenclature) is a member of the seven transmembrane G-protein coupled receptor (GPCR) superfamily. Recent concerns with selective and non-selective COX-1/COX-2 inhibition have exposed an important cardioprotective role for IP in preventing atherothrombosis. Receptor dysfunction (genetic variants) or reduced signaling (COX-2 inhibition) in high cardiovascular risk patients leads to increased cardiovascular events. These clinical ...[more]

PMID: 21707517

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Project description:P2X4 receptors are adenosine triphosphate (ATP)-gated cation channels present on the plasma membrane (PM) and also within intracellular compartments such as vesicles, vacuoles, lamellar bodies (LBs), and lysosomes. P2X4 receptors in microglia are up-regulated in epilepsy and in neuropathic pain; that is to say, their total and/or PM expression levels increase. However, the mechanisms underlying up-regulation of microglial P2X4 receptors remain unclear, in part because it has not been possible to image P2X4 receptor distribution within, or trafficking between, cellular compartments. Here, we report the generation of pH-sensitive fluorescently tagged P2X4 receptors that permit evaluations of cell surface and total receptor pools. Capitalizing on information gained from zebrafish P2X4.1 crystal structures, we designed a series of mouse P2X4 constructs in which a pH-sensitive green fluorescent protein, superecliptic pHluorin (pHluorin), was inserted into nonconserved regions located within flexible loops of the P2X4 receptor extracellular domain. One of these constructs, in which pHluorin was inserted after lysine 122 (P2X4-pHluorin123), functioned like wild-type P2X4 in terms of its peak ATP-evoked responses, macroscopic kinetics, calcium flux, current-voltage relationship, and sensitivity to ATP. P2X4-pHluorin123 also showed pH-dependent fluorescence changes, and was robustly expressed on the membrane and within intracellular compartments. P2X4-pHluorin123 identified cell surface and intracellular fractions of receptors in HEK-293 cells, hippocampal neurons, C8-B4 microglia, and alveolar type II (ATII) cells. Furthermore, it showed that the subcellular fractions of P2X4-pHluorin123 receptors were cell and compartment specific, for example, being larger in hippocampal neuron somata than in C8-B4 cell somata, and larger in C8-B4 microglial processes than in their somata. In ATII cells, P2X4-pHluorin123 showed that P2X4 receptors were secreted onto the PM when LBs undergo exocytosis. Finally, the use of P2X4-pHluorin123 showed that the modulator ivermectin did not increase the PM fraction of P2X4 receptors and acted allosterically to potentiate P2X4 receptor responses. Collectively, our data suggest that P2X4-pHluorin123 represents a useful optical probe to quantitatively explore P2X4 receptor distribution, trafficking, and up-regulation.

Dataset Information

Prostacyclin receptor regulation--from transcription to trafficking.

Publications

Prostacyclin receptor regulation--from transcription to trafficking.

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