Abstract
The generation of the second messengers inositol 1,4,5-trisphosphate (InsP 3) and diacylglycerol (DAG) by phosphoinositide-specific phospholipases C (PLCs) is a key mechanism by which many cellular functions such as intracellular calcium handling or growth and differentiation are modulated. In the myocardium, PLC plays a role in the mediation of positive inotropic effects and is possibly involved in the pathogenesis of myocardial hypertrophy. Among the variety of PLC isozymes known, the PLC βfamily is regulated by heterotrimeric G proteins. The aim of the present study was to identify and to characterize the PLC βisoform present in human myocardium. PLC activity in human myocardial membranes was dependent on the presence of Ca 2+. Interestingly, PLC was markedly stimulated by GTP γS, used as an activator of G proteins. This stimulation was completely abolished by GDP. However, purified α-subunits from retinal transducin ( α t), used as scavengers of free βγ-subunits, did not abolish this effect indicating GTP γS stimulation being mediated by G protein α-subunits. PLC activity was also stimulated by G protein βγ-subunits purified from bovine retina ( βγ t). This stimulation was completely blocked by addition of purified α t. Reverse transcriptions and polymerase chain reactions (RT-PCR) provided evidence for PLC β 1mRNA being expressed in human myocardium, whereas PCR products corresponding to PLC β 2and PLC β 3mRNAs were not detected. It is concluded that PLC β 1mRNA is expressed in human myocardium. The functional properties of human myocardial PLC activity correspond well to the properties established for PLC β 1, i.e. sensitivity to G protein α- as well as βγ-subunits. The presence of other as yet unidentified PLC isozymes is nevertheless possible. The identification of the PLC βisozyme present in human myocardium and the understanding of its regulation by G protein subunits sets the stage for the investigation of possible involvement of this system in the pathophysiology of myocardial hypertrophy.
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