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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension.

Large conductance, Ca(2+)-activated K(+) (BK) channels modulate the excitability and contractile state of arterial smooth muscle. Recently, we demonstrated that during hypertension, expression of the accessory beta1 subunit was decreased relative to the pore-forming alpha subunit of the BK channel. Reduced beta1 subunit expression resulted in BK channels with impaired function due to lowered sensitivity to Ca(2+). Here, we tested the hypothesis that activation of the calcineurin/ NFATc3 signaling pathway down-regulates beta1 expression during angiotensin II- induced hypertension. Consistent with this hypothesis, we found that in vivo administration of angiotensin II-activated calcineurin/ NFATc3 signaling in arterial smooth muscle. During angiotensin II infusion, arterial smooth muscle BK channel function was decreased in wild type (WT) but not in NFATc3 null ( NFATc3(-/-)) mice. Accordingly, beta1 expression was decreased in WT but not in NFATc3(-/-) arteries. Angiotensin II-induced down-regulation of the beta1 subunit required Ca(2+) influx via L-type Ca(2+) channels. However, in the absence of angiotensin II, moderate elevation of [Ca(2+)](i) alone was not sufficient to activate NFAT transcriptional activity and, thus, decrease beta1 subunit expression. Importantly, angiotensin II infusion increased systemic blood pressure to a lower extent in NFATc3(-/-) than in WT mice, indicating that this transcription factor is required for the development of severe hypertension during chronic angiotensin II signaling activation. We conclude that activation of calcineurin and NFATc3 during sustained angiotensin II signaling down-regulates the expression of the beta1 subunit of the BK channel, which in turn contributes to arterial dysfunction and the development of hypertension.[1]


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