| Abstract No.: | C-B3052 |
| Country: | Canada |
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| Title: | ASTROCYTES RESPOND TO NEURONAL ACTIVITY VIA ACTIVATION OF BICARBONATE-RESPONSIVE SOLUBLE ADENYLYL CYCLASE
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| Authors/Affiliations: | 2 Hyun B Choi*; 2 Grant RJ Gordon; 2 Jae K Ryu; 2 James G McLarnon; 1 Lonny R Levin; 1 Jochen Buck; 2 Brian A MacVicar;
1 New York, NY, USA ; 2 University of British Columbia, Vancouver, BC, Canada
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| Content: | We have discovered a novel pathway by which astrocytes detect and respond to changes in neuronal activity that alter external potassium concentrations ([K+]ext) Astrocyte membrane potential is very sensitive to changes in [K+]ext . Increased neuronal activity can raise [K+]ext from controls levels of 3 mM to 5 to 6 mM and to > 15 mM during pathophysiological conditions such as ischemia and spreading depression. Years ago it was reported that the elevated [K+]ext causes astrocyte alkalinization as a result of membrane depolarization which leads to activation of an electrogenic NaHCO3 transporter and thereby increased intracellular bicarbonate (HCO3-) concentrations. A recently cloned new form of adenylyl cyclase (soluble adenylyl cyclase, sAC) has been identified as an enzyme that is activated by HCO3-. Therefore we tested first, whether sAC is present in astrocytes and second, whether sAC is a target for the increased intracellular HCO3- that occurs during raised [K+]ext. Increasing [K+]ext from 2.5 mM to 10 mM raised cAMP levels through a HCO3- dependent activation of sAC and this was significantly reduced only by sAC specific inhibitors, KH7 and 2-hydroxyestrone (2-OH) but not by DDA, an inhibitor of membrane adenylyl cyclase. We investigated, whether cAMP production via sAC activation induces glycogen breakdown and subsequent accumulation of lactate in brain slices. The results show that raising [K+]ext to 10 mM increased glycogen breakdown and accumulation of lactate which was significantly inhibited by KH7 and 2-OH but not by DDA. These results suggest that bicarbonate-responsive sAC is present in astrocytes and may play a critical role in regulating cellular energy substrates in response to increased [K+]ext that occurs during intense synaptic activation and ischemic conditions.
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