Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K<sup>+</sup>Channel Expression and Trafficking

Sandoz, Guillaume; Tardy, Magalie P.; Thümmler, Susanne; Féliciangéli, Sylvain; Lazdunski, Michel; Lesage, Florian

doi:10.1523/jneurosci.1962-08.2008

Cited by 54 publications

(49 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TREK-1 is known to interact with AKAP150, a PKA anchor protein, as well as Mtap2, a microtubule-associated protein (44)(45)(46). Mtap2 enhances TREK-1 current by recruiting channel proteins to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Froese

Breher²,

Waldeyer³

et al. 2012

J. Clin. Invest.

136

455

View full text Add to dashboard Cite

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that the coexpression of both interacting proteins provides additive effects on TREK-1 current (44)(45)(46). Thus, it will be interesting to study the modulation of TREK-1 current in the presence of Popdc proteins and these other TREK-1 interaction partners.…”

Section: Discussionmentioning

confidence: 99%

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Froese

Breher²,

Waldeyer³

et al. 2012

J. Clin. Invest.

136

455

View full text Add to dashboard Cite

show abstract

“…In contrast, TREK1 coassembles poorly with members of other K 2P subfamilies, such as TASK channels. The overlapping expression patterns in the mouse brain (7,28) suggest that heterodimers may form in native tissue. We found that the functional properties of heterodimers are distinct from the functional properties of the homodimers, thereby providing an added mechanism for functional diversity.…”

Section: Discussionmentioning

confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

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

View full text Add to dashboard Cite

Twik-related K + channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K + channel (TRAAK) form the TREK subfamily of two-pore-domain K + (K 2P ) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K 2P channels.potassium channels | single-molecule fluorescence | leak current | combinatorial diversity | heteromerization

show abstract

“…Mtap2 attaches to the amino acid stretch between E335 and Q360 on the COOH-terminal tail of TREK-1, which is clearly distinct from the AKAP150 binding site. This allows simultaneous binding of AKAP150 and Mtap2 to the channel with an additive intensifying effect on TREK current (297).…”

Section: Interaction With Partner Proteinsmentioning

confidence: 99%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

736

769

View full text Add to dashboard Cite

Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

show abstract

Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K⁺Channel Expression and Trafficking

Cited by 54 publications

References 43 publications

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Contact Info

Product

Resources

About

Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K+Channel Expression and Trafficking

Cited by 54 publications

References 43 publications

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

Contact Info

Product

Resources

About

Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K⁺Channel Expression and Trafficking

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels