Abstract
The activation of BK channels by Ca2+ is highly cooperative, with small changes in intracellular Ca2+ concentration having large effects on open probability (P0). Here we examine the mechanism of cooperative activation of BK channels by Ca2+. Each of the four subunits of BK channels has a large intracellular COOH terminus with two different high-affinity Ca2+ sensors: an RCK1 sensor (D362/D367) located on the RCK1 (regulator of conductance of K+) domain and a Ca-bowl sensor located on or after the RCK2 domain. To determine interactions among these Ca2+ sensors, we examine channels with eight different configurations of functional high-affinity Ca2+ sensors on the four subunits. We find that the RCK1 sensor and Ca bowl contribute about equally to Ca 2+ activation of the channel when there is only one high-affinity Ca2+ sensor per subunit. We also find that an RCK1 sensor and a Ca bowl on the same subunit are much more effective in increasing Po than when they are on different subunits, indicating positive intrasubunit cooperativity. If it is assumed that BK channels have a gating ring similar to MthK channels with alternating RCK1 and RCK2 domains and that the Ca2+ sensors act at the flexible (rather than fixed) interfaces between RCK domains, then a comparison of the distribution of Ca2+ sensors with the observed responses suggest that the interface between RCK1 and RCK2 domains on the same subunit is flexible. On this basis, intrasubunit cooperativity arises because two high-affinity Ca2+ sensors acting across a flexible interface are more effective in opening the channel than when acting at separate interfaces. An allosteric model incorporating intrasubunit cooperativity nested within intersubunit cooperativity could approximate the Po vs. Ca2+ response for eight possible subunit configurations of the high-affinity Ca2+ sensors as well as for three additional configurations from a previous study.
| Original language | English |
|---|---|
| Pages (from-to) | 389-404 |
| Number of pages | 16 |
| Journal | Journal of General Physiology |
| Volume | 128 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2 2006 |
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ASJC Scopus subject areas
- Physiology
Cite this
Intra- and intersubunit cooperativity in activation of BK channels by Ca2+. / Qian, Xiang; Niu, Xiaowei; Magleby, Karl.
In: Journal of General Physiology, Vol. 128, No. 4, 02.10.2006, p. 389-404.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intra- and intersubunit cooperativity in activation of BK channels by Ca2+
AU - Qian, Xiang
AU - Niu, Xiaowei
AU - Magleby, Karl
PY - 2006/10/2
Y1 - 2006/10/2
N2 - The activation of BK channels by Ca2+ is highly cooperative, with small changes in intracellular Ca2+ concentration having large effects on open probability (P0). Here we examine the mechanism of cooperative activation of BK channels by Ca2+. Each of the four subunits of BK channels has a large intracellular COOH terminus with two different high-affinity Ca2+ sensors: an RCK1 sensor (D362/D367) located on the RCK1 (regulator of conductance of K+) domain and a Ca-bowl sensor located on or after the RCK2 domain. To determine interactions among these Ca2+ sensors, we examine channels with eight different configurations of functional high-affinity Ca2+ sensors on the four subunits. We find that the RCK1 sensor and Ca bowl contribute about equally to Ca 2+ activation of the channel when there is only one high-affinity Ca2+ sensor per subunit. We also find that an RCK1 sensor and a Ca bowl on the same subunit are much more effective in increasing Po than when they are on different subunits, indicating positive intrasubunit cooperativity. If it is assumed that BK channels have a gating ring similar to MthK channels with alternating RCK1 and RCK2 domains and that the Ca2+ sensors act at the flexible (rather than fixed) interfaces between RCK domains, then a comparison of the distribution of Ca2+ sensors with the observed responses suggest that the interface between RCK1 and RCK2 domains on the same subunit is flexible. On this basis, intrasubunit cooperativity arises because two high-affinity Ca2+ sensors acting across a flexible interface are more effective in opening the channel than when acting at separate interfaces. An allosteric model incorporating intrasubunit cooperativity nested within intersubunit cooperativity could approximate the Po vs. Ca2+ response for eight possible subunit configurations of the high-affinity Ca2+ sensors as well as for three additional configurations from a previous study.
AB - The activation of BK channels by Ca2+ is highly cooperative, with small changes in intracellular Ca2+ concentration having large effects on open probability (P0). Here we examine the mechanism of cooperative activation of BK channels by Ca2+. Each of the four subunits of BK channels has a large intracellular COOH terminus with two different high-affinity Ca2+ sensors: an RCK1 sensor (D362/D367) located on the RCK1 (regulator of conductance of K+) domain and a Ca-bowl sensor located on or after the RCK2 domain. To determine interactions among these Ca2+ sensors, we examine channels with eight different configurations of functional high-affinity Ca2+ sensors on the four subunits. We find that the RCK1 sensor and Ca bowl contribute about equally to Ca 2+ activation of the channel when there is only one high-affinity Ca2+ sensor per subunit. We also find that an RCK1 sensor and a Ca bowl on the same subunit are much more effective in increasing Po than when they are on different subunits, indicating positive intrasubunit cooperativity. If it is assumed that BK channels have a gating ring similar to MthK channels with alternating RCK1 and RCK2 domains and that the Ca2+ sensors act at the flexible (rather than fixed) interfaces between RCK domains, then a comparison of the distribution of Ca2+ sensors with the observed responses suggest that the interface between RCK1 and RCK2 domains on the same subunit is flexible. On this basis, intrasubunit cooperativity arises because two high-affinity Ca2+ sensors acting across a flexible interface are more effective in opening the channel than when acting at separate interfaces. An allosteric model incorporating intrasubunit cooperativity nested within intersubunit cooperativity could approximate the Po vs. Ca2+ response for eight possible subunit configurations of the high-affinity Ca2+ sensors as well as for three additional configurations from a previous study.
UR - http://www.scopus.com/inward/record.url?scp=33749013044&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749013044&partnerID=8YFLogxK
U2 - 10.1085/jgp.200609486
DO - 10.1085/jgp.200609486
M3 - Article
C2 - 17001085
AN - SCOPUS:33749013044
VL - 128
SP - 389
EP - 404
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 4
ER -