The NH2 terminus of RCK1 domain regulates Ca2+-dependent BKCa channel gating

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States
The Journal of General Physiology (Impact Factor: 4.79). 10/2005; 126(3):227-41. DOI: 10.1085/jgp.200509321
Source: PubMed


Large conductance, voltage- and Ca2+-activated K+ (BK(Ca)) channels regulate blood vessel tone, synaptic transmission, and hearing owing to dual activation by membrane depolarization and intracellular Ca2+. Similar to an archeon Ca2+-activated K+ channel, MthK, each of four alpha subunits of BK(Ca) may contain two cytosolic RCK domains and eight of which may form a gating ring. The structure of the MthK channel suggests that the RCK domains reorient with one another upon Ca2+ binding to change the gating ring conformation and open the activation gate. Here we report that the conformational changes of the NH2 terminus of RCK1 (AC region) modulate BK(Ca) gating. Such modulation depends on Ca2+ occupancy and activation states, but is not directly related to the Ca2+ binding sites. These results demonstrate that AC region is important in the allosteric coupling between Ca2+ binding and channel opening. Thus, the conformational changes of the AC region within each RCK domain is likely to be an important step in addition to the reorientation of RCK domains leading to the opening of the BK(Ca) activation gate. Our observations are consistent with a mechanism for Ca2+-dependent activation of BK(Ca) channels such that the AC region inhibits channel activation when the channel is at the closed state in the absence of Ca2+; Ca2+ binding and depolarization relieve this inhibition.

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Available from: Gayathri Krishnamoorthy,
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    • "Taken these results together, it is likely that the C-Linker and AC region of Slo1 may interact with the cytosolic domain of the β2 subunit either directly or through an allosteric mechanism. Previous studies show that changes in the length of the C-Linker alter Ca 2+ sensitivity of the channel (Niu et al., 2004), while mutations in the AC region revealed an allosteric network important for Ca 2+ dependence of channel gating (Krishnamoorthy et al., 2005;Yang et al., 2010). Our results further support the important role of the C-Linker and AC region in mediating the coupling between Ca 2+ binding and channel opening and show that the β2 subunit may modulate Ca 2+ sensitivity by altering such coupling. "
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    • "), and is important in determining Ca 2+ sensitivity (Krishnamoorthy et al., 2005). Furthermore, both the putative Ca 2+ -binding site D367 and the mutation mD369G are situated within the AC region so that the mutation may alter its structure to affect Ca 2+ sensitivity. "
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