Small Conductance Ca2+-activated K+ Channels and Calmodulin

Lee, Cynthia Wei-Sheng; Ngo-Anh, Thu Jennifer; Bruening‐Wright, Andrew; Maylie, James; Adelman, John P.

doi:10.1074/jbc.m302091200

Cited by 93 publications

(88 citation statements)

References 46 publications

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“…1 and 4). CaM is not only essential for gating but is also required for channel assembly and trafficking (28). Our data demonstrate that targeting or anchoring of SK2 channel at the plasma membrane requires the binding of ␣-actinin2, which crosslinks actin filaments to stabilize the muscle contractile apparatus and signal transduction.…”

Section: ␣-Actinin2mentioning

confidence: 75%

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

Lü

Timofeyev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The importance of proper ion channel trafficking is underpinned by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface. Conceptually, it is reasonable to suggest that the function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane, which is determined jointly by the secretory and endocytic pathways. Yet the precise mechanisms of the entire ion channel trafficking pathway remain unknown. Here, we directly demonstrate that proper membrane localization of a smallconductance Ca 2ϩ -activated K ؉ channel (SK2 or KCa2.2) is dependent on its interacting protein, ␣-actinin2, a major F-actin crosslinking protein. SK2 channel localization on the cell-surface membrane is dynamically regulated, and one of the critical steps includes the process of cytoskeletal anchoring of SK2 channel by its interacting protein, ␣-actinin2, as well as endocytic recycling via early endosome back to the cell membrane. Consequently, alteration of these components of SK2 channel recycling results in profound changes in channel surface expression. The importance of our findings may transcend the area of K ؉ channels, given that similar cytoskeletal interaction and anchoring may be critical for the membrane localization of other ion channels in neurons and other excitable cells.ion channel trafficking ͉ early endosome ͉ cardiac myocytes ͉ small conductance Ca 2ϩ -activated K ϩ channel ͉ calmodulin binding domain T he function of ion channels depends critically on the precise number and subcellular localization of the channel proteins on the cell-surface membrane (1, 2). The steady-state cell-surface expression of ion channels is intricately and dynamically governed by the anterograde (forward) and retrograde trafficking (2, 3). Ion channel molecules are first synthesized in the endoplasmic reticulum (ER), assembled and processed, then trafficked to the membrane where they function. Trafficking of ion channel proteins to the surface membrane involves a series of tightly regulated events coordinated by ER resident proteins, microtubules, transport vesicle and Golgi apparatus, the actin cytoskeleton, myosins, and anchoring proteins (2). The importance of correct ion channel trafficking is highlighted by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface (4-8).Small-conductance Ca 2ϩ -activated K ϩ (SK or K Ca 2) channels belong to a family of Ca 2ϩ -activated K ϩ channels (K Ca ) that have been reported from a wide variety of cells (9-11). SK channels represent a highly unique family of K ϩ channels, in that they are directly gated by changes in intracellular Ca 2ϩ concentration and hence function to integrate changes in Ca 2ϩ concentration with changes in K ϩ conductance and membrane potentials. SK channels have been shown to mediate afterhyperpolarizations in neurons (9, 12, 13) and action potential repolarization in cardiac tissues (14,15). Prev...

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Section: ␣-Actinin2mentioning

confidence: 75%

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

Lü

Timofeyev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…We found that CaM provides a Ca 2ϩ -dependent acceleration of channel trafficking to distal regions of dendrites in hippocampal neurons. This adds to a growing list of examples in which CaM, as a constitutive subunit, modulates steps in channel biosynthesis such as trafficking of SK K ϩ channels (Joiner et al, 2001;Lee et al, 2003) or assembly of KCNQ1 K ϩ channels (Ghosh et al, 2006;Shamgar et al, 2006). For Ca 2ϩ / CaM acceleration of ␣ 1C trafficking, two results suggest that the mechanism of action for CaM most likely involves an interaction with the CaM binding pocket.…”

Section: Discussionmentioning

confidence: 93%

Ca²⁺/Calmodulin Regulates Trafficking of Ca_V1.2 Ca²⁺Channels in Cultured Hippocampal Neurons

Wang¹,

George²,

Kim³

et al. 2007

J. Neurosci.

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“…Although a great deal has been learned about the second messenger-dependent regulation of these KCa channels in terms of altering P o (15)(16)(17)(18)(19)(20)(21), much less information exists regarding the mechanisms by which N is determined. We (20,(22)(23)(24) and others (25)(26)(27) have identified numerous motifs in the N and C termini of KCa2.3 and KCa3.1, which are required for the proper assembly and anterograde trafficking of these channels to the plasma membrane. However, to date, no studies have defined the retrograde transport of KCa2.3 or KCa3.1 from the plasma membrane.…”

mentioning

confidence: 76%

“…To determine which portion of KCa2.3 dictates its long half-life, and presumably its recycling, we generated two chimeras in which either the entire cytoplasmic C terminus of KCa3.1 (Arg 287 -Lys 427 ) was appended onto S6 of KCa2.3 (Fig. 10A, KCa2.3-287KCa3.1) or the N terminus of KCa3.1 (Met 1 -Ala 26 ) was appended to S1 of KCa2.3 (Fig. 10B, 26KCa3.1-KCa2.3).…”

Section: Recycling Of Kca23 Is Dependent Upon Rab35 and The Rab35 Gamentioning

confidence: 99%

Recycling of the Ca2+-activated K+ Channel, KCa2.3, Is Dependent upon RME-1, Rab35/EPI64C, and an N-terminal Domain

Gao

Balut

Bailey

et al. 2010

Journal of Biological Chemistry

123

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Regulation of the number ofFurthermore, the effect of EPI64C was dependent upon its GTPase-activating proteins activity. Co-immunoprecipitation studies confirmed an association between KCa2.3 and both Rab35 and RME-1. In contrast to KCa2.3, KCa3.1 was rapidly endocytosed and degraded in an RME-1 and Rab35-independent manner. A series of N-terminal deletions identified a 12-amino acid region, Gly 206 -Pro 217 , as being required for the rapid recycling of KCa2.3. Deletion of Gly 206 -Pro 217 had no effect on the association of KCa2.3 with Rab35 but significantly decreased the association with RME-1. These represent the first studies elucidating the mechanisms by which KCa2.3 is maintained at the plasma membrane.

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Small Conductance Ca2+-activated K+ Channels and Calmodulin

Abstract: Small conductance Ca2؉ -activated K ؉ channels (SK channels) are heteromeric complexes of pore-forming ␣ subunits and constitutively bound calmodulin (CaM).

Cited by 93 publications

References 46 publications

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

Ca²⁺/Calmodulin Regulates Trafficking of Ca_V1.2 Ca²⁺Channels in Cultured Hippocampal Neurons

Recycling of the Ca2+-activated K+ Channel, KCa2.3, Is Dependent upon RME-1, Rab35/EPI64C, and an N-terminal Domain

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Small Conductance Ca2+-activated K+ Channels and Calmodulin

Abstract: Small conductance Ca2؉ -activated K ؉ channels (SK channels) are heteromeric complexes of pore-forming ␣ subunits and constitutively bound calmodulin (CaM).

Cited by 93 publications

References 46 publications

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+channel (SK2 channel)

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+channel (SK2 channel)

Ca2+/Calmodulin Regulates Trafficking of CaV1.2 Ca2+Channels in Cultured Hippocampal Neurons

Recycling of the Ca2+-activated K+ Channel, KCa2.3, Is Dependent upon RME-1, Rab35/EPI64C, and an N-terminal Domain

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α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca²⁺-activated K⁺channel (SK2 channel)

Ca²⁺/Calmodulin Regulates Trafficking of Ca_V1.2 Ca²⁺Channels in Cultured Hippocampal Neurons