Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

Ito, Akihiko; Ichiyanagi, Naoki; Ikeda, Yuki; Hagiyama, Man; Inoué, Takao; Kimura, Keiko; Sakurai, Minami A.; Hamaguchi, Kazuyuki; Murakami, Yoshinori

doi:10.4161/isl.18675

Cited by 27 publications

(20 citation statements)

References 30 publications

(46 reference statements)

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“…Such selectivity is appropriate for proper islet functioning, particularly since beta and alpha cells function antagonistically under most conditions. Gap junctions have been claimed to connect different islet cell types [258], which are occasionally coupled in culture [259, 260]. However, direct evidence that alpha and beta cells make bona fide gap junction plaques has not yet been provided, and tracer studies do not support the occurrence of a large coupling between these cells [261–263].…”

Section: Cell Interactions In the Endocrine Pancreasmentioning

confidence: 99%

Protein-Mediated Interactions of Pancreatic Islet Cells

Meda

2013

Scientifica

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The islets of Langerhans collectively form the endocrine pancreas, the organ that is soley responsible for insulin secretion in mammals, and which plays a prominent role in the control of circulating glucose and metabolism. Normal function of these islets implies the coordination of different types of endocrine cells, noticeably of the beta cells which produce insulin. Given that an appropriate secretion of this hormone is vital to the organism, a number of mechanisms have been selected during evolution, which now converge to coordinate beta cell functions. Among these, several mechanisms depend on different families of integral membrane proteins, which ensure direct (cadherins, N-CAM, occludin, and claudins) and paracrine communications (pannexins) between beta cells, and between these cells and the other islet cell types. Also, other proteins (integrins) provide communication of the different islet cell types with the materials that form the islet basal laminae and extracellular matrix. Here, we review what is known about these proteins and their signaling in pancreatic β-cells, with particular emphasis on the signaling provided by Cx36, given that this is the integral membrane protein involved in cell-to-cell communication, which has so far been mostly investigated for effects on beta cell functions.

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Section: Cell Interactions In the Endocrine Pancreasmentioning

confidence: 99%

Protein-Mediated Interactions of Pancreatic Islet Cells

Meda

2013

Scientifica

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“…In T2DM pancreata, the decrease in full-length CADM1 was associated with its absence from the cell membrane in both alpha and beta cells (Table 1). Previously, we reported that CADM1 contributes to gap junctional communication among mouse islet alpha cells and that decreased expression of CADM1 on the cell membrane of mouse alpha cells resulted in the supernormal secretion of glucagon, suggesting that mouse CADM1 may serve as a volume limiter of glucagon secretion by sustaining alpha cell-cell attachment necessary for efficient gap junctional communication [17]. Similarly in human T2DM pancreata, downregulation of full-length CADM1 may impair gap junctional communication among alpha cells and thus underlie the hyperglucagonemia often observed in T2DM patients [40].…”

Section: Discussionmentioning

confidence: 95%

“…In mice, CADM1 expression is restricted to alpha cells, whereas it is expressed equally in the four cell types (alpha, beta, D, and PP) that constitute human islet cells [16]. CADM1 appears to play a significant role in hormone secretion by mediating islet cell-cell and islet cell-nerve interactions through trans -homophilic binding [16], [17]. Recent studies have shown that CADM1 expression is regulated by post-transcriptional mechanisms, including glycosylation and proteolytic cleavage, referred to as shedding [18], [19].…”

Section: Introductionmentioning

confidence: 99%

Increased Ectodomain Shedding of Cell Adhesion Molecule 1 from Pancreatic Islets in Type 2 Diabetic Pancreata: Correlation with Hemoglobin A1c Levels

et al. 2014

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Pulmonary emphysema and type 2 diabetes mellitus (T2DM), both caused by lifestyle factors, frequently concur. Respectively, the diseases affect lung alveolar and pancreatic islet cells, which express cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member. Protease-mediated ectodomain shedding of full-length CADM1 produces C-terminal fragments (CTFs) with proapoptotic activity. In emphysematous lungs, the CADM1 shedding rate and thus the level of CTFs in alveolar cells increase. In this study, CADM1 expression in islet cells was examined by western blotting. Protein was extracted from formalin-fixed, paraffin-embedded sections of pancreata isolated from patients with T2DM (n = 12) or from patients without pancreatic disease (n = 8) at autopsy. After adjusting for the number of islet cells present in the adjacent section, we found that full-length CADM1 decreased in T2DM islets, while ectodomain shedding increased. Hemoglobin A1c levels, measured when patients were alive, correlated inversely with full-length CADM1 levels (P = 0.041) and positively with ectodomain shedding rates (P = 0.001). In immunofluorescence images of T2DM islet cells, CADM1 was detected in the cytoplasm, but not on the cell membrane. Consistently, when MIN6-m9 mouse beta cells were treated with phorbol ester and trypsin to induce shedding, CADM1 immunostaining was diffuse in the cytoplasm. When a form of CTFs was exogenously expressed in MIN6-m9 cells, it localized diffusely in the cytoplasm and increased the number of apoptotic cells. These results suggest that increased CADM1 ectodomain shedding contributes to blood glucose dysregulation in T2DM by decreasing full-length CADM1 and producing CTFs that accumulate in the cytoplasm and promote apoptosis of beta cells. Thus, this study has identified a molecular alteration shared by pulmonary emphysema and T2DM.

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“…3B). As in ␣-cells then, CADM1 in islet ␤-cells appears to function as an inhibitor of hormone release (23).…”

Section: Cadm Expression In Human and Rat Isletsmentioning

confidence: 99%

“…In ␣-cells, CADM1 helps constrain glucagon secretion (23). Enhanced insulin secretion in CADM1 global knockout mice suggests that CADM1 similarly inhibits insulin exocytosis (38).…”

mentioning

confidence: 99%

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

Zhang

Caldwell

Mirbolooki

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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N, Chessler SD. Extracellular CADM1 interactions influence insulin secretion by rat and human islet ␤-cells and promote clustering of syntaxin-1. Am J Physiol Endocrinol Metab 310: E874 -E885, 2016. First published April 12, 2016 doi:10.1152/ajpendo.00318.2015-Contact between ␤-cells is necessary for their normal function. Identification of the proteins mediating the effects of ␤-cell-to-␤-cell contact is a necessary step toward gaining a full understanding of the determinants of ␤-cell function and insulin secretion. The secretory machinery of the ␤-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the transcellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such transcellular interactions, important for both synaptic and ␤-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here, we tested the role of another synaptic cleft protein, CADM1, in insulinoma cells and in rat and human islet ␤-cells. We found that CADM1 is a predominant CADM isoform in ␤-cells. In INS-1 cells and primary ␤-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we found that CADM1 also influences insulin secretion in a transcellular manner. We asked whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on ␤-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing ␤-cell dysfunction in diabetes.cell adhesion molecule 1; SynCam; pancreatic islet; insulin secretion

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Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

Cited by 27 publications

References 30 publications

Protein-Mediated Interactions of Pancreatic Islet Cells

Protein-Mediated Interactions of Pancreatic Islet Cells

Increased Ectodomain Shedding of Cell Adhesion Molecule 1 from Pancreatic Islets in Type 2 Diabetic Pancreata: Correlation with Hemoglobin A1c Levels

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

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