Abstract 231: Uncovering the Mechanism and Function of Newly Discovered KCNQ1-Transporter Complexes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Daniel L Neverisky ◽  
Geoffrey W Abbott
Keyword(s):  
Complex Formation ◽  
Cardiac Function ◽  
Glucose Transporter ◽  
Beta Subunits ◽  
Lone Atrial Fibrillation ◽  
Potassium Efflux ◽  
Regulatory Subunits ◽  
And Function ◽  
Solute Transporters ◽  
Normal Cardiac Function

The KCNQ1 voltage-gated potassium channel is essential for human ventricular repolarization, permitting potassium efflux from excited cardiomyocytes to end each action potential and repolarize the heart. In cardiomyocytes, KCNQ1 is modulated by interaction with beta-subunits from the KCNE gene family, each of which significantly alters KCNQ1 channel function. KCNQ1 mutations are the most common identified genetic basis for Long QT syndrome (LQTS) and are also associated with lone atrial fibrillation (AF). The sodium-dependent myo-inositol transporter 1 (SMIT1) mediates cellular uptake of myo-inositol, an essential osmolyte that also represents an important substrate for phosphatidylinositol signaling pathways that regulate a plethora of ion channels including those essential for human cardiac function. We recently discovered that KCNQ1 can form heteromeric, co-regulatory complexes with Na+-coupled solute transporters including SMIT1, SMIT2 and glucose transporter SGLT1. These findings represent the first reported example of formation of an ion channel-solute transporter complex. Having discovered KCNQ1-SMIT1 complexes in mouse choroid plexus epithelium, we are currently investigating whether these types of complexes occur in the heart, how their function is altered by the various cardiac-expressed KCNE regulatory subunits or by arrhythmia-associated mutations, and which parts of KCNQ1 coordinate complex formation. Here, we present evidence of KCNQ1-SMIT1 co-assembly in pig heart based on co-immunoprecipitation experiments. Using KCNQ1-KCNQ4 chimeras we also begin to define which specific regions of KCNQ1 are required for complex formation with SMIT1. Finally, we present data showing the effects of SMIT1 on complexes formed by KCNQ1 and KCNE1, 2 and 3. KCNQ1-transporter complexes provide a potential hub for electrochemical crosstalk in normal cardiac function and in arrhythmogenesis.

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

2001 ◽  
Vol 281 (5) ◽  
pp. H1938-H1945 ◽  
Author(s):  
Chari Y. T. Hart ◽  
John C. Burnett ◽  
Margaret M. Redfield
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Rise ◽  
Left Ventricular ◽  
Lv Function ◽  
Ketamine Anesthesia ◽  
The Difference ◽  
And Function ◽  
Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

Investigation of the structure and function of the human erythrocyte glucose transporter by proteolytic dissection

1987 ◽  
Vol 905 (2) ◽  
pp. 295-310 ◽  
Author(s):  
Michael T. Cairns ◽  
Javier Alvarez ◽  
Maria Panico ◽  
Angel F. Gibbs ◽  
Howard R. Morris ◽  
...  
Keyword(s):  
Human Erythrocyte ◽  
Glucose Transporter ◽  
Structure And Function ◽  
And Function

scholarly journals Cardiorenal Connection: Uninephrectomy Results in Cardiac Gene Changes Despite Normal Cardiac Function

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Fernando L Martin ◽  
Brenda K Huntley ◽  
Gerald E Harders ◽  
Gregory Gilman ◽  
John C Burnett
Keyword(s):  
Cardiac Function ◽  
Cardiac Gene ◽  
Normal Cardiac Function

scholarly journals Regulatory γ1 subunits defy symmetry in functional modulation of BK channels

2018 ◽  
Vol 115 (40) ◽  
pp. 9923-9928 ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Manu Ben Johny ◽  
Xiao-Ming Xia ◽  
Christopher J. Lingle
Keyword(s):  
Single Channel ◽  
Regulatory Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Bk Channels ◽  
Bk Channel ◽  
Single Type ◽  
Regulatory Subunits ◽  
And Function

Structural symmetry is a hallmark of homomeric ion channels. Nonobligatory regulatory proteins can also critically define the precise functional role of such channels. For instance, the pore-forming subunit of the large conductance voltage and calcium-activated potassium (BK, Slo1, or KCa1.1) channels encoded by a single KCa1.1 gene assembles in a fourfold symmetric fashion. Functional diversity arises from two families of regulatory subunits, β and γ, which help define the range of voltages over which BK channels in a given cell are activated, thereby defining physiological roles. A BK channel can contain zero to four β subunits per channel, with each β subunit incrementally influencing channel gating behavior, consistent with symmetry expectations. In contrast, a γ1 subunit (or single type of γ1 subunit complex) produces a functionally all-or-none effect, but the underlying stoichiometry of γ1 assembly and function remains unknown. Here we utilize two distinct and independent methods, a Forster resonance energy transfer-based optical approach and a functional reporter in single-channel recordings, to reveal that a BK channel can contain up to four γ1 subunits, but a single γ1 subunit suffices to induce the full gating shift. This requires that the asymmetric association of a single regulatory protein can act in a highly concerted fashion to allosterically influence conformational equilibria in an otherwise symmetric K+channel.

Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function

Development ◽  
2000 ◽  
Vol 127 (13) ◽  
pp. 2883-2895 ◽  
Author(s):  
M. Gannon ◽  
M.K. Ray ◽  
K. Van Zee ◽  
F. Rausa ◽  
R.H. Costa ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Endocrine Cells ◽  
Spatial Organization ◽  
Glucose Transporter ◽  
Cell Function ◽  
Regulatory Element ◽  
Cell Physiology ◽  
Pancreatic Ducts ◽  
And Function

We used transgenesis to explore the requirement for downregulation of hepatocyte nuclear factor 6 (HNF6) expression in the assembly, differentiation, and function of pancreatic islets. In vivo, HNF6 expression becomes downregulated in pancreatic endocrine cells at 18. 5 days post coitum (d.p.c.), when definitive islets first begin to organize. We used an islet-specific regulatory element (pdx1(PB)) from pancreatic/duodenal homeobox (pdx1) gene to maintain HNF6 expression in endocrine cells beyond 18.5 d.p.c. Transgenic animals were diabetic. HNF6-overexpressing islets were hyperplastic and remained very close to the pancreatic ducts. Strikingly, alpha, delta, and PP cells were increased in number and abnormally intermingled with islet beta cells. Although several mature beta cell markers were expressed in beta cells of transgenic islets, the glucose transporter GLUT2 was absent or severely reduced. As glucose uptake/metabolism is essential for insulin secretion, decreased GLUT2 may contribute to the etiology of diabetes in pdx1(PB)-HNF6 transgenics. Concordantly, blood insulin was not raised by glucose challenge, suggesting profound beta cell dysfunction. Thus, we have shown that HNF6 downregulation during islet ontogeny is critical to normal pancreas formation and function: continued expression impairs the clustering of endocrine cells and their separation from the ductal epithelium, disrupts the spatial organization of endocrine cell types within the islet, and severely compromises beta cell physiology, leading to overt diabetes.

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