Inositol phospholipids localized to caveolae in rat heart are regulated by α1-adrenergic receptors and by ischemia-reperfusion

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Abstract
Postischemic reperfusion of rat or mouse hearts causes generation of inositol ( 1 , 4 , 5 )trisphosphate [Ins( 1 , 4 , 5 )P3] and the initiation of arrhythmias. In the current study we investigated the possibility that the enhanced Ins( 1 , 4 , 5 )P3generation in postischemic reperfusion was associated with an increased availability of the precursor lipid phosphatidylinositol( 4 , 5 )bisphosphate (PIP2) for α1-adrenergic receptor-activated phospholipase C (PLC). Isolated-perfused rat hearts were labeled with [3H]inositol and subjected to ischemia-reperfusion or stimulation with norepinephrine under normoxic conditions. Caveolar fractions were prepared by buoyant density sucrose gradient centrifugation. [3H]PIP2was concentrated in caveolae, along with Gαq and PLCβ1b. Caveolae contained only 27.3 ± 6.9% (means ± SE, n = 6) of the total α1-adrenergic receptor complement of the heart. These did not migrate to PIP2-containing caveolar fractions with norepinephrine stimulation under normoxic conditions, even though caveolar PIP2was depleted. In contrast, [3H]PIP2in caveolae increased during 2 min of reperfusion, independently of norepinephrine release and thus of α1-adrenergic receptor activation. The increased PIP2in the caveolar fractions where signaling proteins are concentrated may be critical for the heightened generation of Ins( 1 , 4 , 5 )P3in early reperfusion.