Signal transduction pathways associated with alpha1-adrenoceptor subtypes in cells and tissues including human...

The complexity of the signal transduction pathways linked to alpha1A-adrenoceptors are becoming clearer. At one time it was thought that the alpha1A-subtype was linked to the influx of extracellular Ca2+ while the alpha1B-subtype was linked via inositol phosphate formation to the release of intracellular Ca2. However the coupling of the alpha1-adrenoceptors to G-proteins leads to the activation of a number of different effector enzymes which produce intracellular second messengers and alterations in biological activity. One area of diversity is in the many forms of the Galpha, beta, gamma heterotrimeric G-proteins which confer specificity towards certain effectors. All alpha1-adrenoceptor subtypes have been shown to couple to phospholipase C in many cells and tissues leading to the breakdown of PiP2 to give IP3, which releases intracellular Ca2+, and diacylglycerol, which stimulates protein kinase C. Additional effectors which can couple to alpha1-adrenoceptors include phospholipase D, adenylate cyclase and the mitogen-activated protein kinase pathway. The latter involves a longer term response and causes increased cell growth and may be important in, for example, the prostate as well as in vascular smooth muscle and the heart. In human prostate alpha1-adrenoceptor activation leads to the release of intracellular Ca2+ from ryanodine-sensitive store followed by an influx of extracellular Ca2+, a mechanism different from that linked to the same receptor subtype in several other smooth muscles. Therefore a given alpha1-subtype may be coupled to a variety of different signal transduction mechanisms in different systems. Further, there may be different effector mechanisms linked to alpha1-subtypes in a given cell or tissue e.g. phospholipase C and mitogen-activated protein kinase. An increased understanding of the complexity of signal transduction mechanisms and the elucidation of the details in a particular tissue will open up new possibilities for therapeutic interventions.