Figure 1.

Cell model illustrating β₂-adrenergic and insulin-mediated regulatory pathways for K⁺ uptake in skeletal muscle. β₂-Adrenergic stimulation and insulin both lead to K⁺ uptake by stimulating the activity of the Na⁺-K⁺-ATPase pump primarily in skeletal muscle, but they do so through different signaling pathways. β₂-Adrenergic stimulation leads to increased pump activity through a cAMP- and protein kinase A–dependent pathway. Insulin binding to its receptor leads to phosphorylation of the insulin receptor substrate protein (IRS-1), which in turns binds to phosphatidylinositide 3-kinase (PI3-K). The IRS/1-PI3-K interaction leads to activation of 3-phosphoinositide dependent protein kinase-1. The stimulatory effect of insulin on glucose uptake and K⁺ uptake diverge at this point. A serine/threonine protein kinase–dependent pathway is responsible for membrane insertion of the glucose transporter protein GLUT4, whereas activation of atypical protein kinase C leads to membrane insertion of the Na⁺-K⁺-ATPase pump. Not shown is that insulin stimulates pump activity by increasing cell Na⁺ brought about by a stimulatory effect on the Na⁺-H⁺ antiporter.