Potential Signal Transduction Regulation by HDL of the β2-Adrenergic Receptor Pathway. Implications in Selected...

The main atheroprotective mechanism of high-density lipoprotein (HDL) has been regarded as reverse cholesterol transport, whereby cholesterol from peripheral tissues is removed and transported to the liver for elimination. Although numerous additional atheroprotective mechanisms have been suggested, the role of HDL in modulating signal transduction of cell membrane-bound receptors has received little attention to date. This potential was recently highlighted following the identification of a polymorphism in the adenylyl cyclase 9 gene (ADCY9) that was shown to be a determining factor in the risk of cardiovascular (CV) events in patients treated with the HDL-raising compound dalcetrapib. Indeed, ADCY9 is part of the signaling pathway of the β2-adrenergic receptor (β2-AR) and both are membrane-bound proteins affected by changes in membrane-rich cholesterol plasma membrane domains (caveolae). Numerous G-protein-coupled receptors (GPCRs) and ion channels are affected by caveolae, with caveolae composition acting as a 'signalosome'. Polymorphisms in the genes encoding ADCY9 and β2-AR are associated with response to β2-agonist drugs in patients with asthma, malaria and with sickle cell disease. Crystallization of the β2-AR has found cholesterol tightly bound to transmembrane structures of the receptor. Cholesterol has also been shown to modulate the activity of this receptor. Apolipoprotein A1 (ApoA1), the major protein component of HDL, destabilizes and removes cholesterol from caveolae with high affinity through interaction with ATP-binding cassette transporter. Furthermore, β2-AR activity may be affected by ApoA1/HDL-targeted therapies. Taken together, these observations suggest a common pathway that potentially links a primary HDL function to the regulation of signal transduction.