Altered Aβ Formation and Long-Term Potentiation in a Calsenilin Knock-Out

Lilliehöök, Christina; Bozdagi, Ozlem; Yao, Jun; Gomez‐Ramirez, Manuel; Zaidi, Nikhat F.; Wasco, Wilma; Gandy, Sam; Santucci, Anthony C.; Haroutunian, Vahram; Huntley, George W.; Buxbaum, Joseph D.

doi:10.1523/jneurosci.23-27-09097.2003

Cited by 98 publications

(120 citation statements)

References 41 publications

(50 reference statements)

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“…Enhanced GFP (EGFP, Clontech) was coexpressed with the channel to assess transfection efficiency and to identify expressing cells for voltage clamp experiments (26). One day prior to transfection, cells were plated onto cover slips.…”

Section: Methodsmentioning

confidence: 99%

KChIP3 Rescues the Functional Expression of Shal Channel Tetramerization Mutants

Kunjilwar

Strang

DeRubeis

et al. 2004

Journal of Biological Chemistry

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KChIP proteins regulate Shal, Kv4.x, channel expression by binding to a conserved sequence at the N terminus of the subunit. The binding of KChIP facilitates a redistribution of Kv4 protein to the cell surface, producing a large increase in current along with significant changes in channel gating kinetics. Recently we have shown that mutants of Kv4.2 lacking the ability to bind an intersubunit Zn 2؉ between their T1 domains fail to form functional channels because they are unable to assemble to tetramers and remain trapped in the endoplasmic reticulum. Here we find that KChIPs are capable of rescuing the function of Zn 2؉ site mutants by driving the mutant subunits to assemble to tetramers. Thus, in addition to known trafficking effects, KChIPs play a direct role in subunit assembly by binding to monomeric subunits within the endoplasmic reticulum and promoting tetrameric channel assembly. Zn 2؉ -less Kv4.2 channels expressed with KChIP3 demonstrate several distinct kinetic changes in channel gating, including a reduced time to peak and faster entry into the inactivated state as well as extending the time to recover from inactivation by 3-4 fold.The formation of voltage-gated potassium (Kv) 1 channels is a multistep process with many different interactions and folding events required to form the completed channel (1). The common functional core of all Kv channels assembles as a tetramer of pore-forming ␣-subunits. This tetramer is the core of the future ion channel signal transduction complex, but additional folding steps as well as interactions with auxiliary proteins occur before the final functional channel complex at the cell surface is formed. Many auxiliary subunit proteins that bind to Kv ␣-subunits have been identified, but precisely when these interactions occur during channel complex formation and what role these interactions play in helping the channels to assemble, traffic, and function are topics of great interest (1-4). Through the use of heterologous expression systems and mutagenesis studies, we can expose many of these important interactions and folding events, and reveal the processes by which Kv channel complexes form. A comparison of channel expression and functional properties with and without specific auxiliary proteins reveals how these different processes contribute to the formation and function of ion channel complexes.An early step in Kv channel formation involves the tetramerization of the ␣-subunit T1 domains at the cytoplasmic N terminus of the protein (5-7). For Kv4.2 channels, a critical component of the T1 domain interaction involves the coordination of an intersubunit Zn 2ϩ ion found on non-Shaker type Kv channel T1 domains (8 -10). Although Zn 2ϩ binding sites are common in proteins, intersubunit Zn 2ϩ binding sites, as found in the T1 domain, are relatively rare. To determine what functions might be regulated by the T1 intersubunit Zn 2ϩ site, we generated a series of mutations to the Zn 2ϩ coordination residues and tested them for cell surface expression (8). We found that mut...

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Section: Methodsmentioning

confidence: 99%

KChIP3 Rescues the Functional Expression of Shal Channel Tetramerization Mutants

Kunjilwar

Strang

DeRubeis

et al. 2004

Journal of Biological Chemistry

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“…Cite this article as Cold Spring Harb Perspect Biol 2010;2:a004085 (Lilliehook et al 2003). Although many of the KChIPs and their isoforms may have overlapping functions, some differences between them are beginning to emerge (Holmqvist et al 2002;Venn et al 2008).…”

Section: Calcium Sensor Proteins In Neuronal Functionmentioning

confidence: 99%

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

McCue

Haynes²,

Burgoyne

2010

Cold Spring Harbor Perspectives in Biology

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“…The KChIP proteins regulate the gating kinetics of Shaker K ϩ channels (34). DREAM͞calse-nilin binds to specific DNA sequence elements in the prodynorphin and c-fos genes (35) and serves as a transcriptional repressor for pain modulation (79,80). Hence, the physiological functions of the NCS proteins are highly diverse and nonoverlapping.…”

Section: Functional Diversity Of Ncs and S100 Proteinsmentioning

confidence: 99%

Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: Two ways to promote multifunctionality

Ikura

Ames

2006

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

236

202

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Calcium signaling pathways control a variety of cellular events such as gene transcription, protein phosphorylation, nucleotide metabolism, and ion transport. These pathways often involve a large number of calcium-binding proteins collectively known as the calmodulin or EF-hand protein superfamily. Many EF-hand proteins undergo a large conformational change upon binding to Ca 2؉ and target proteins. All members of the superfamily share marked sequence homology and similar structural features required to sense Ca 2؉ . Despite such structural similarities, the functional diversity of EF-hand calcium-binding proteins is extraordinary. Calmodulin itself can bind >300 different proteins, and the many members of the neuronal calcium sensor and S100 protein families collectively recognize a largely different set of target proteins. Recent biochemical and structural studies of many different EF-hand proteins highlight remarkable similarities and variations in conformational responses to the common ligand Ca 2؉ and their respective cellular targets. In this review, we examine the essence of molecular recognition activities and the mechanisms by which calmodulin superfamily proteins control a wide variety of Ca 2؉ signaling processes.

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Altered Aβ Formation and Long-Term Potentiation in a Calsenilin Knock-Out

Cited by 98 publications

References 41 publications

KChIP3 Rescues the Functional Expression of Shal Channel Tetramerization Mutants

KChIP3 Rescues the Functional Expression of Shal Channel Tetramerization Mutants

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: Two ways to promote multifunctionality

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