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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Stimulation of astrocyte Na⁺/H⁺ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2

Departments of ¹Neurosurgery and ²Physiology, University of Wisconsin Medical School, Madison, Wisconsin; and ³Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio

Submitted 3 March 2005 ; accepted in final form 13 May 2005

We recently reported that Na⁺/H⁺ exchanger isoform 1 (NHE1) activity in astrocytes is stimulated and leads to intracellular Na⁺ loading after oxygen and glucose deprivation (OGD). However, the underlying mechanisms for this stimulation of NHE1 activity and its impact on astrocyte function are unknown. In the present study, we investigated the role of the ERK1/2 pathway in NHE1 activation. NHE1 activity was elevated by 75% in NHE1^+/+ astrocytes after 2-h OGD and 1-h reoxygenation (REOX). The OGD/REOX-mediated stimulation of NHE1 was partially blocked by 30 µM PD-98059. Increased expression of phosphorylated ERK1/2 was detected in NHE1^+/+ astrocytes after OGD/REOX. Moreover, stimulation of NHE1 activity disrupted not only Na⁺ but also Ca²⁺ homeostasis via reverse-mode operation of Na⁺/Ca²⁺ exchange. OGD/REOX led to a 103% increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in NHE1^+/+ astrocytes in the presence of thapsigargin. Inhibition of NHE1 activity with the NHE1 inhibitor HOE-642 decreased OGD/REOX-induced elevation of [Ca²⁺]_i by 73%. To further investigate changes of Ca²⁺ signaling, bradykinin-mediated Ca²⁺ release was evaluated. Bradykinin-mediated intracellular Ca²⁺ transient in NHE1^+/+ astrocytes was increased by 84% after OGD/REOX. However, in NHE1^–/– astrocytes or NHE1^+/+ astrocytes treated with HOE-642, the bradykinin-induced Ca²⁺ release was increased by only 34%. Inhibition of the reverse mode of Na⁺/Ca²⁺ exchange abolished OGD/REOX-mediated Ca²⁺ rise. Together, our data suggest that ERK1/2 is involved in activation of NHE1 in astrocytes after in vitro ischemia. NHE1-mediated Na⁺ accumulation subsequently alters Ca²⁺ homeostasis via Na⁺/Ca²⁺ exchange.

intracellular pH; cortical astrocytes; sodium/calcium exchange; intracellular sodium ion

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