an assay system using cultured pancreatic islet cells [28]. Moreover, Gsα-L appears to release GDP ~2-fold faster than Gsα-S [29], and consistent with that finding, study of fusion proteins involving the β2-adrenergic receptor and either Gsα-L or Gsα-S has shown higher constitutive activity of the receptor when it is associated with Gsα-L [30]. In addition, differences in the subcellular trafficking of these two variants have been reported in response to activation by agonist, forskolin (a direct activator of adenylyl cyclase), or GTPγS (a stable GTP analog) [31-33]. Currently, it remains unclear whether these differences translate into biologically significant effects, such as divergence in the variety of effectors and/or the efficiency of effector activation. An important recent finding regarding the long and short Gsα forms is that, for the first time, an inactivating mutation in exon 3 has been identified in a patient with pseudohypoparathyroidism type-Ia [34], a disorder known to be caused by inactivating mutations in Gsα-coding GNAS exons (see below). The patient with the exon 3 mutation has an apparently mild form of this disorder, consistent with the disruption of only one of the two main Gsα variants, i.e. Gsα-L [34]. It is conceivable that, depending on the effector
