Abstract
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 small-conductance Ca2+-activated K+ channel (SK2 or K Ca2.2) is dependent on its interacting protein, α-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, α-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 18402-18407 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 106 |
| Issue number | 43 |
| DOIs | |
| State | Published - 2009 |
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Keywords
- Calmodulin binding domain
- Cardiac myocytes
- Early endosome
- Ion channel trafficking
- Small conductance Ca-activated K channel
ASJC Scopus subject areas
- General
Cite this
α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel). / Lu, Ling; Timofeyev, Valeriy; Li, Ning; Rafizadeh, Sassan; Singapuri, Anil; Harris, Todd R.; Chiamvimonvat, Nipavan.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 43, 2009, p. 18402-18407.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel)
AU - Lu, Ling
AU - Timofeyev, Valeriy
AU - Li, Ning
AU - Rafizadeh, Sassan
AU - Singapuri, Anil
AU - Harris, Todd R.
AU - Chiamvimonvat, Nipavan
PY - 2009
Y1 - 2009
N2 - 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 small-conductance Ca2+-activated K+ channel (SK2 or K Ca2.2) is dependent on its interacting protein, α-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, α-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.
AB - 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 small-conductance Ca2+-activated K+ channel (SK2 or K Ca2.2) is dependent on its interacting protein, α-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, α-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.
KW - Calmodulin binding domain
KW - Cardiac myocytes
KW - Early endosome
KW - Ion channel trafficking
KW - Small conductance Ca-activated K channel
UR - http://www.scopus.com/inward/record.url?scp=70849100291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70849100291&partnerID=8YFLogxK
U2 - 10.1073/pnas.0908207106
DO - 10.1073/pnas.0908207106
M3 - Article
C2 - 19815520
AN - SCOPUS:70849100291
VL - 106
SP - 18402
EP - 18407
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 43
ER -