Ultrastructure and Regulation of Lateralized Connexin43 in the Failing Heart

Hesketh, Geoffrey G.; Shah, Manish H.; Halperin, Victoria L.; Cooke, Carol; Akar, Fadi G.; Yen, Timothy; Kass, David A.; Machamer, Carolyn E.; Eyk, Jennifer E. Van; Tomaselli, Gordon F.

doi:10.1161/circresaha.108.182147

Cited by 127 publications

(147 citation statements)

References 56 publications

(69 reference statements)

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“…This is also supported by the observation that a large proportion of delocalized Cx43 are nonphosphorylated, given the role of the phosphorylation processes in the regulation of channel properties, assembly and targeting in junctional plaques (218,404). Electron microscopic study reveals an enhanced internalization of Cx43 at the lateral membrane in the failing ventricular myocardium of dog (167). Internalized Cx43 are incorporated in multilamellar membrane structures resembling double membrane vesicles previously termed annular gap junctions and which are the result of a clathrin-dependent endocytosis of large portions of or entire gap junction plaques (117,332).…”

Section: A Delocalization Of Connexinsmentioning

confidence: 62%

“…hERG channels are internalized by the caveolar pathway in HEK 293 cells (261), such as the Nav1.5 channel in ventricular tissue (164). The role of clathrin in the internalization of connexins has been clearly established in both cell lines and myocardium (152,167,168,332). Interestingly, the internalization pathway used by cardiac ion channels appears to be dependent on the cell type considered.…”

Section: Endocytosis In the Myocardiummentioning

confidence: 99%

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Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Balse

Steele

Abriel

et al. 2012

Physiological Reviews

107

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Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine-tune ion channel expression and control cardiac excitability.

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Section: A Delocalization Of Connexinsmentioning

confidence: 62%

Section: Endocytosis In the Myocardiummentioning

confidence: 99%

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Balse

Steele

Abriel

et al. 2012

Physiological Reviews

107

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“…vATPase assembly and, indirectly, activity can be assessed by measuring the translocation of V1 subunits to membranes using immunoblot analysis. Acini were pretreated with AICAR (2 mM) or compound C (20 M) followed by cerulein stimulation for 15 min, an incubation time previously determined to be the optimum for vATPase translocation (13). Pretreatment with AICAR tended to decrease V1 translocation, whereas pretreatment with compound C tended to increase V1 translocation (Fig.…”

Section: With In Vivo Cerulein Hyperstimulation Ampk Subunits Translmentioning

confidence: 93%

Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation

Shugrue

Alexandre

Villalvilla

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Shugrue CA, Alexandre M, Diaz de Villalvilla A, Kolodecik TR, Young LH, Gorelick FS, Thrower EC. Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. Am J Physiol Gastrointest Liver Physiol 303: G723-G732, 2012. First published July 26, 2012; doi:10.1152/ajpgi.00082.2012.-The premature activation of digestive enzyme zymogens in the pancreatic acinar cell is an important initiating event in acute pancreatitis. We have previously demonstrated that vacuolar ATPase (vATPase) activity is required for zymogen activation. Adenosine monophosphate-activated protein kinase (AMPK) regulates vATPase function in kidney and epididymal clear cells. To determine whether AMPK could affect pancreatitis responses, its effects were first examined in a cellular model of pancreatitis, cerulein-hyperstimulated (100 nM) pancreatic acini. This treatment caused a prominent increase in trypsin and chymotrypsin activities. Pretreatment with AICAR or metformin (AMPK activators) or compound C (an AMPK inhibitor) reduced or increased cerulein-induced zymogen activation, respectively. The association of the vATPase E subunit with membranes, a marker of its activation, tended to be inversely related to AMPK activity (assessed by AICAR and compound C treatments). Cerulein treatment did not change AMPK (␣ and ␤) levels but did lead to an increase in its activation (phosphorylation of Thr172) and induced the time-dependent translocation of the enzyme to a Triton-insoluble compartment. Basal in vivo studies showed that AMPK was widely distributed between membrane and soluble fractions generated by differential centrifugation. After cerulein hyperstimulation, AMPK levels selectively decreased in fractions containing the highest levels of active zymogens. These studies suggest that AMPK activity has a protective role in the pancreatic acinar cell that inhibits zymogen activation in the basal state, and this AMPK effect is reduced during pancreatitis. Therapies that prevent the selective reduction of AMPK in compartments that support zymogen activation could reduce injury during pancreatitis. pancreatic acini; vacuolar ATPase THE PANCREATIC ACINAR CELL comprises over 90% of the exocrine pancreas and synthesizes and secretes the enzymes needed to digest nutrients. Many of the digestive enzymes are stored in the acinar cells as inactive zymogens that become activated only after reaching the small intestine. Premature activation of these zymogens within acinar cells appears to have a critical role in initiating acute pancreatitis (17). Experimental models of acute pancreatitis have been developed in which isolated acinar cells or whole animals are treated with supraphysiological concentrations of cerulein (an orthologue of the hormone cholecystokinin) to induce the early stages of the disease.AMP-activated kinase (AMPK) is a heterotrimeric serine/ threonine kinase, composed of ␣-, ␤-, and ␥-subunits, with the ␣-subunit possessing the catalytic kinase domain. Phosphorylation of the Thr172 resid...

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“…It appears that all of the identifi ed processes of internalization terminate in the lysosomal degradation of Cx43 (Guan and Ruch, 1996;Hesketh et al, 2010;Laing & Beyer, 1995;Laing et al, 1998;Laing et al, 1997;Leithe et al, 2006;Leithe et al, 2009;Lichtenstein et al, 2011;Murray et al, 1981;Naus et al, 1993;Qin et al, 2003;Sasaki & Garant, 1986;Simeckova et al, 2009;Thomas et al, 2003;Fong et al, 2012). However, there is also evidence that a portion of the Cx43 that is internalized may return to the plasma membrane by recycling mechanisms (Boassa et al, 2010;Gilleron et al, 2011;VanSlyke & Musil, 2005;Xie et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been shown that gap junctions, which are aggregated in plaques at the plasma membrane, can be internalized into one of the two adjoining cells as unique double-membrane endocytic structures called annular gap junctions (AGJ) or connexosomes (Gumpert et al, 2008;Piehl et al, 2007;Gilleron et al, 2011;Falk et al, 2009). Following internalization from the plasma membrane, connexins are degraded by endolysosomal and autophagic mechanisms (Hesketh et al, 2010;Lichtenstein et al, 2011;Bejarano et al, 2012;Leithe et al, 2011;Falk et al, 2009;Laing et al, 1997;Leithe et al, 2006;Leithe et al, 2009;Qin et al, 2003;VanSlyke & Musil, 2005;Berthoud et al, 2000;Laird, 2006;Laird et al, 1995). These mechanisms along with proteasome-mediated ER-associated degradation regulate the rapid turnover and relatively short, 1.5 -5 hour half-life of connexins VanSlyke & Musil, 2002).…”

Section: Introductionmentioning

confidence: 99%

The connexin43-interacting protein, CIP85, mediates the internalization of connexin43 from the plasma membrane

Cochrane

Lau

2013

Cell Communication & Adhesion

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CIP85 was previously identifi ed as a connexin43 (Cx43)-interacting protein that is ubiquitously expressed in multiple mammalian tissues and cell types. The interaction between the SH3 domain of CIP85 and a proline-rich region of Cx43 has previously been associated with an increased rate of Cx43 turnover through lysosomal mechanisms. This report presents biochemical and immunofl uorescence evidence that overexpression of CIP85 reduced the presence of Cx43 in gap junction plaques at the plasma membrane. Furthermore, this effect was dependent upon the interaction of CIP85 with Cx43 at the plasma membrane. These results indicate that CIP85 increases Cx43 turnover by accelerating the internalization of Cx43 from the plasma membrane. CIP85 was also observed to interact with clathrin, which suggested a role for CIP85 in the clathrin-mediated internalization of Cx43.

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Ultrastructure and Regulation of Lateralized Connexin43 in the Failing Heart

Cited by 127 publications

References 56 publications

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation

The connexin43-interacting protein, CIP85, mediates the internalization of connexin43 from the plasma membrane

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