Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 3, Pages 1073-1078Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708823105
Keywords
calcium; cerebral blood flow; mouse; nitric oxide; phosphorylation
Categories
Funding
- NHLBI NIH HHS [HL18974, P01 HL018974] Funding Source: Medline
- NINDS NIH HHS [NS37853, R01 NS037853] Funding Source: Medline
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The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional brain imaging signals. Nitric oxide, a vasodilator released by NMDA receptor activation, is critical for the flow increase, but the factors linking NMDA receptor activity to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation. tPA acts by facilitating neuronal nitric oxide release, but this effect does not involve enhancement of NMDA currents or the associated intracellular Ca2+ rise. Rather, the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal nitric oxide synthase. These findings unveil a previously unrecognized role of tPA in vital homeostatic mechanisms coupling NMDA receptor signaling With nitric oxide synthesis and local cerebral perfusion.
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