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Some Ca2 channels, including voltage-gated L-type channels, let through more Ca2 per opening when they are used frequently. This positive feedback, known as facilitation, allows fast-beating cardiac cells, for instance, to beat harder (as during exercise). The new findings reveal that local retention of a Ca2 /calmodulin-dependent kinase, CaMKII, is behind this ability.
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CaMKII is activated by autophosphorylation in response to Ca2 /calmodulin. The authors find that CaMKII then tethers itself to the pore-forming 1C subunit of the L-type channel, which is abundant in heart muscle. Even upon dephosphorylation, CaMKII lingers at the channel., T- s$ q& q7 [1 y$ U
! n# V/ V" u0 k; @From this position, the kinase can up-regulate channel activity when Ca2 influx is frequent. The authors show that active CaMKII phosphorylates two regions of 1C that were previously found to regulate channel activity. Unlike NMDAR-bound CaMKII, which is constitutively active, 1C-bound CaMKII still depends on Ca2 /calmodulin. This difference might explain why NMDARs are up-regulated for the long term by a brief stimulus, whereas full activity of voltage-gated channels requires repeated activation.
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3 J5 F, R: ]( u6 c0 O7 QTethering to 1C is necessary for facilitation, even though the channel can be phosphorylated by free kinase. The close proximity may allow the kinase to outdo channel-defacilitating phosphatases. Only when Ca2 influx is frequent, and CaMKII activity is repeatedly high, can CaMKII win the fight.(Active Ca2 channels, according to Hudmo) |
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发表于 2009-3-6 08:52
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