PIP
            <sub>2</sub>
            binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome

Donaldson, Matthew R.; Jensen, Judy L; Tristani‐Firouzi, Martin; Tawil, Rabi; Bendahhou, Saı̈d; Suarez, William A.; Cobo, Ana Maria; Poza, Juan José; Behr, Elijah R.; Wagstaff, Joseph; Szepetowski, Pierre; Pereira, Sandrine; Mozaffar, Tahseen; Escolar, Diana M.; Fu, Ying‐Hui; Ptáček, Louis J.

doi:10.1212/01.wnl.0000072261.14060.47

Cited by 179 publications

(169 citation statements)

References 25 publications

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“…ENaC Lacking the Region following the Second Trans-membrane Domain in ␥-ENaC Does Not Respond to PI (3,4,5)P 3 -The results in Fig. 5 are from experiments directly testing the idea that the region just following the second trans-membrane domain in ␥-ENaC is critical to PI(3,4,5)P 3 regulation of the channel.…”

Section: Deletion Of the Region Following The Second Trans-membrane Dmentioning

confidence: 99%

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Pochynyuk

Staruschenko

Tong

et al. 2005

Journal of Biological Chemistry

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Membrane phospholipids, such as phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ), are signaling molecules that can directly modulate the activity of ion channels, including the epithelial Na ؉ channel (ENaC). Whereas PI(3,4,5)P 3 directly activates ENaC, its binding site within the channel has not been identified. We identify here a region of ␥-mENaC just following the second trans-membrane domain (residues 569 -583) important to PI(3, Direct regulation of ion channel activity by phospholipid signaling molecules is becoming widely appreciated (reviewed in Ref. 1). This mechanism for ion channel modulation is recognized to be physiologically important for its disruption, in some instances, leads to disease (e.g. Bartter and Andersen syndromes) (2-5). Diverse types of ion channels, including those composed of subunits having only two trans-membrane domains, such as ENaC 2 and inwardly rectifying K ϩ channels (Kir), as well as those with subunits having multiple (four or six) membranespanning domains, such as KCNQ, HERG, and two pore domain K ϩ channels, and transient receptor potential and cyclic nucleotide-gated channels, are modulated by phospholipids (6 -13). Phospholipids, such as PI(4,5)P 2 and PI(3,4,5)P 3 , directly interact with these channels to modulate gating (6,9,14). ENaC is a heteromeric channel composed of three distinct but similar subunits: ␣, ␤, and ␥ (15, 16). Each subunit has an amino-and carboxylterminal cytosolic domain separated by two trans-membrane domains and a large extracellular region. ENaC serves an essential physiological function, since its activity is limiting for Na ϩ absorption across many epithelia, including that in the distal renal nephron (reviewed in Refs. 17-19). Thus, ENaC is well positioned to influence system Na ϩ balance and blood pressure. Indeed, gain and loss of function mutations in ENaC lead to inheritable forms of hypertension and hypotension, respectively, associated with inappropriate salt conservation and wasting at the kidney (20, 21). In addition, ENaC plays a critical role in hydration and fluid reabsorption across many mucosal membranes. Deletion and overexpression of ENaC correspondingly lead to excessively wet and dry air spaces with associated disease (21, 22). The mineralocorticoid aldosterone increases ENaC activity. Several lines of evidence suggest a role for PI(3,4,5)P 3 signaling in regulation of ENaC by aldosterone and other hormones, such as insulin (23-30). Aldosterone increases PI3-K activity and production of its phospholipid products (29). In some preparations, aldosterone activates PI3-K to augment ENaC activity via transcriptional control of the upstream PI3-Kregulator, K-Ras (31-33). Both K-Ras and PI3-K increase ENaC open probability (31)(32)(33). Moreover, we recently demonstrated a direct effect of PI(3,4,5)P 3 on ENaC to increase channel open probability (33).4The phospholipid binding site in several types of ion channels, particularly that for PI(4,5)P 2 binding to Kir and transient receptor potential channels, is becoming cle...

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Section: Deletion Of the Region Following The Second Trans-membrane Dmentioning

confidence: 99%

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Pochynyuk

Staruschenko

Tong

et al. 2005

Journal of Biological Chemistry

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“…The phospholipid PIP 2 activates Kir2.1, and many mutations associated with Andersen-Tawil syndrome show reduced affinity of the channel for PIP 2 rather than complete channel absence. 66 Gain-of-function mutations have been identified in individuals presenting with short QT syndrome and families suffering from AF. 67 Kir2.1 deficient mice die shortly after birth; whereas Kir2.2¡/¡ mice are viable and display no gross abnormalities.…”

Section: Kir21mentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype.

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“…5,9,20 Phosphatidylinositol 4,5-bisphosphate binding residues of Kir2.1 are common targets of mutations causing ATS1. 21 Most mutations have a dominant negative effect on potassium channel current. The mutation with the most potent dominant effect is the T75R missense mutation.…”

Section: Genetics Of Ats Animal Models and Other Potential Clinicalmentioning

confidence: 99%

Management and Treatment of Andersen-Tawil Syndrome (ATS)

Sansone

Tawil

2007

Neurotherapeutics

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Summary: Andersen-Tawil syndrome (ATS) is characterized by periodic paralysis, cardiac arrhythmias, and distinct facial and skeletal features. The majority of patients with ATS (ATS1) have point mutations in the KCNJ2 gene, which encodes the inward-rectifying potassium channel known as Kir2.1. The skeletal muscle and cardiac symptoms are accounted for, in most cases, by a dominant negative effect of the mutations on potassium channel current, resulting in prolonged depolarization of the action potential. Mechanisms of disruption of channel function include abnormal trafficking and assembly of second messengers such as phosphatidylinositol 4,5-bisphosphate, abnormal gating of the channel, and incorrect folding of the Kir2.1 protein. Less apparent is the mechanism by which these mutations account for the typical facial and skeletal abnormalities. The concomitant involvement of cardiac and skeletal muscle in ATS poses unique treatment and management challenges. Because of differences in cardiac and skeletal muscle physiology, drugs that may have a beneficial effect on cardiac function may have a detrimental effect on skeletal muscle and vice versa. We review the clinical, laboratory, and genetic features of this disorder with particular emphasis on treatment and management.

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PIP ₂ binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome

Cited by 179 publications

References 25 publications

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Cardiac ion channels

Management and Treatment of Andersen-Tawil Syndrome (ATS)

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PIP 2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome

Cited by 179 publications

References 25 publications

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel

Cardiac ion channels

Management and Treatment of Andersen-Tawil Syndrome (ATS)

Contact Info

Product

Resources

About

PIP ₂ binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome