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Regions of KCNQ K(+) channels controlling functional expression.

Choveau FS, Shapiro MS - Front Physiol (2012)

Bottom Line: Despite similar structures, KCNQ2 and KCNQ3 homomers yield small current amplitudes compared to other KCNQ homomers and KCNQ2/3 heteromers.The second mechanism suggests networks of interactions between the pore helix and the selectivity filter (SF), and between the pore helix and the S6 domain that govern KCNQ current amplitudes.Here, we summarize the role of these different regions in expression of functional KCNQ channels.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Health Science Center at San Antonio San Antonio, TX, USA.

ABSTRACT
KCNQ1-5 α-subunits assemble to form K(+) channels that play critical roles in the function of numerous tissues. The channels are tetramers of subunits containing six transmembrane domains. Each subunit consists of a pore region (S5-pore-S6) and a voltage-sensor domain (S1-S4). Despite similar structures, KCNQ2 and KCNQ3 homomers yield small current amplitudes compared to other KCNQ homomers and KCNQ2/3 heteromers. Two major mechanisms have been suggested as governing functional expression. The first involves control of channel trafficking to the plasma membrane by the distal part of the C-terminus, containing two coiled-coiled domains, required for channel trafficking and assembly. The proximal half of the C-terminus is the crucial region for channel modulation by signaling molecules such as calmodulin (CaM), which may mediate C- and N-terminal interactions. The N-terminus of KCNQ channels has also been postulated as critical for channel surface expression. The second mechanism suggests networks of interactions between the pore helix and the selectivity filter (SF), and between the pore helix and the S6 domain that govern KCNQ current amplitudes. Here, we summarize the role of these different regions in expression of functional KCNQ channels.

No MeSH data available.


Model showing the role of N-C terminus interaction in the regulation of KCNQ2-3 channels by CaM. (A) Representation of KCNQ2 and KCNQ3 mutant (A315T) channels (helices C and D in the C-terminus were omitted for clarity) with the N-C terminus interaction (horizontal red lines) and the additional interaction between the distal end of the N-terminus and the C-terminus (orange) in KCNQ3 mutant (A315T) and probably wild-type KCNQ3 channels. (B) CaM binding induces downregulation of current amplitudes, which is depicted by smaller K+ fluxes (red arrows), accompagnied by a stronger N-C terminus interaction. (C) Helix A of KCNQ3 confering resistance to CaM on channel function (adapted from Etzioni et al., 2011).
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Figure 2: Model showing the role of N-C terminus interaction in the regulation of KCNQ2-3 channels by CaM. (A) Representation of KCNQ2 and KCNQ3 mutant (A315T) channels (helices C and D in the C-terminus were omitted for clarity) with the N-C terminus interaction (horizontal red lines) and the additional interaction between the distal end of the N-terminus and the C-terminus (orange) in KCNQ3 mutant (A315T) and probably wild-type KCNQ3 channels. (B) CaM binding induces downregulation of current amplitudes, which is depicted by smaller K+ fluxes (red arrows), accompagnied by a stronger N-C terminus interaction. (C) Helix A of KCNQ3 confering resistance to CaM on channel function (adapted from Etzioni et al., 2011).

Mentions: Another study suggests CaM to be involved in intramolecular regulation involving N-C termini interactions (Etzioni et al., 2011). Based on pull-down assays, FRET analysis and patch-clamp experiments, a model has been proposed depicting the regulation of KCNQ2 and KCNQ3 channels by CaM (Figure 2). In wild-type KCNQ2 and KCNQ3 (A315T) channels, an N-C termini interaction occurs (Figure 2A). An additional interaction is formed in KCNQ3 (A315T) between the distal part of the N-terminus and the C-terminus (Figure 2A, left). In that model, CaM binding to helices A and B downregulates wild-type KCNQ2, which is accompanied by a stronger N-C termini interaction (Figure 2B). Similar results were found in a chimeric KCNQ3 channel containing helix A of KCNQ2, showing that the interaction between the distal ends of the N-C termini does not underlie downregulation of channels by CaM (Figure 2B, left). In contrast, replacement of helix A of KCNQ2 by that of KCNQ3 rendered channels resistant to CaM, preventing closer N-C terminus proximity as in KCNQ3 (A315T) channels (Figure 2C).


Regions of KCNQ K(+) channels controlling functional expression.

Choveau FS, Shapiro MS - Front Physiol (2012)

Model showing the role of N-C terminus interaction in the regulation of KCNQ2-3 channels by CaM. (A) Representation of KCNQ2 and KCNQ3 mutant (A315T) channels (helices C and D in the C-terminus were omitted for clarity) with the N-C terminus interaction (horizontal red lines) and the additional interaction between the distal end of the N-terminus and the C-terminus (orange) in KCNQ3 mutant (A315T) and probably wild-type KCNQ3 channels. (B) CaM binding induces downregulation of current amplitudes, which is depicted by smaller K+ fluxes (red arrows), accompagnied by a stronger N-C terminus interaction. (C) Helix A of KCNQ3 confering resistance to CaM on channel function (adapted from Etzioni et al., 2011).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Model showing the role of N-C terminus interaction in the regulation of KCNQ2-3 channels by CaM. (A) Representation of KCNQ2 and KCNQ3 mutant (A315T) channels (helices C and D in the C-terminus were omitted for clarity) with the N-C terminus interaction (horizontal red lines) and the additional interaction between the distal end of the N-terminus and the C-terminus (orange) in KCNQ3 mutant (A315T) and probably wild-type KCNQ3 channels. (B) CaM binding induces downregulation of current amplitudes, which is depicted by smaller K+ fluxes (red arrows), accompagnied by a stronger N-C terminus interaction. (C) Helix A of KCNQ3 confering resistance to CaM on channel function (adapted from Etzioni et al., 2011).
Mentions: Another study suggests CaM to be involved in intramolecular regulation involving N-C termini interactions (Etzioni et al., 2011). Based on pull-down assays, FRET analysis and patch-clamp experiments, a model has been proposed depicting the regulation of KCNQ2 and KCNQ3 channels by CaM (Figure 2). In wild-type KCNQ2 and KCNQ3 (A315T) channels, an N-C termini interaction occurs (Figure 2A). An additional interaction is formed in KCNQ3 (A315T) between the distal part of the N-terminus and the C-terminus (Figure 2A, left). In that model, CaM binding to helices A and B downregulates wild-type KCNQ2, which is accompanied by a stronger N-C termini interaction (Figure 2B). Similar results were found in a chimeric KCNQ3 channel containing helix A of KCNQ2, showing that the interaction between the distal ends of the N-C termini does not underlie downregulation of channels by CaM (Figure 2B, left). In contrast, replacement of helix A of KCNQ2 by that of KCNQ3 rendered channels resistant to CaM, preventing closer N-C terminus proximity as in KCNQ3 (A315T) channels (Figure 2C).

Bottom Line: Despite similar structures, KCNQ2 and KCNQ3 homomers yield small current amplitudes compared to other KCNQ homomers and KCNQ2/3 heteromers.The second mechanism suggests networks of interactions between the pore helix and the selectivity filter (SF), and between the pore helix and the S6 domain that govern KCNQ current amplitudes.Here, we summarize the role of these different regions in expression of functional KCNQ channels.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Health Science Center at San Antonio San Antonio, TX, USA.

ABSTRACT
KCNQ1-5 α-subunits assemble to form K(+) channels that play critical roles in the function of numerous tissues. The channels are tetramers of subunits containing six transmembrane domains. Each subunit consists of a pore region (S5-pore-S6) and a voltage-sensor domain (S1-S4). Despite similar structures, KCNQ2 and KCNQ3 homomers yield small current amplitudes compared to other KCNQ homomers and KCNQ2/3 heteromers. Two major mechanisms have been suggested as governing functional expression. The first involves control of channel trafficking to the plasma membrane by the distal part of the C-terminus, containing two coiled-coiled domains, required for channel trafficking and assembly. The proximal half of the C-terminus is the crucial region for channel modulation by signaling molecules such as calmodulin (CaM), which may mediate C- and N-terminal interactions. The N-terminus of KCNQ channels has also been postulated as critical for channel surface expression. The second mechanism suggests networks of interactions between the pore helix and the selectivity filter (SF), and between the pore helix and the S6 domain that govern KCNQ current amplitudes. Here, we summarize the role of these different regions in expression of functional KCNQ channels.

No MeSH data available.