P2 purinergic receptors and mechanical strain signal to glycogen synthase kinase‐3beta independently of protein kinase B/Akt in astrocytes

Abstract

Glycogen synthase kinase (GSK)-3 was initially identified as an enzyme that regulates glycogen synthesis in response to insulin, but more recent studies indicate that it is also involved in a number of cellular processes, including cell survival, cell cycle regulation, proliferation and differentiation. Because extracellular ATP exerts trophic actions on astrocytes, we investigated a possible signaling linkage from P2 purinergic receptors to GSK3β. When ATP was added to primary cultures of rat cortical astrocytes, phosphorylation of Ser9 on GSK3β was increased and GSK3 activity was decreased. Agonist studies revealed that that both metabotropic P2Y and ionotropic P2X receptors signal to Ser9-GSK3β. Signaling studies revealed that P2 receptors are independently coupled to GSK3β, Akt and ERK, and that phosphorylation of Ser9-GSK3β is dependent on protein kinase C (PKC). Mechanical strain, which releases ATP, also stimulated Ser9 phosphorylation and this was attenuated by blockade of P2 receptors. These studies indicate that P2 receptors are coupled to GSK3β by a PKC-dependent pathway and suggest that purinergic signaling contributes to the regulation of GSK3β functions such as glycogen metabolism in astrocyte-neuron interactions as well as the response of astrocytes to CNS injury upon release of ATP. (Supported by Dept. Veteran Affairs & NIH.)