beta-blocker reverses inhibition of beta-2 adrenergic receptor resensitization by hypoxia
Sun, Y.; Gupta, M. K.; Stenson, K.; Mohan, M. L.; Wanner, N.; Asosinght, K.; Erzurum, S.; Naga Prasad, S. N.
Show abstract
Ischemia/hypoxia is major underlying cause for heart failure and stroke. Although beta-adrenergic receptor ({beta}AR) is phosphorylated in response to hypoxia, less is known about the underlying mechanisms. Hypoxia results in robust GRK2-mediated {beta}2AR phosphorylation but does not cause receptor internalization. However, hypoxia leads to significant endosomal-{beta}2AR phosphorylation accompanied by inhibition of {beta}2AR-associated protein phosphatase 2A (PP2A) activity impairing resensitization. Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) impedes resensitization by phosphorylating endogenous inhibitor of protein phosphatase 2A, I2PP2A that inhibits PP2A activity. Hypoxia increased PI3K{gamma} activity leading to significant phosphorylation of I2PP2A resulting in inhibition of PP2A and consequently resensitization. Surprisingly, {beta}-blocker abrogated hypoxia-mediated {beta}2AR phosphorylation instead of phosphorylation in normoxia. Subjecting mice to hypoxia leads to significant cardiac dysfunction and {beta}2AR phosphorylation showing conservation of non-canonical hypoxia-mediated pathway in vivo. These findings provide mechanistic insights on hypoxia-mediated {beta}AR dysfunction which is rescued by {beta}-blocker and will have significant implications in heart failure and stroke.
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