ELKS/Voltage-Dependent Ca2+ Channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β Cells

Ohara‐Imaizumi, Mica; Aoyagi, Kyota; Yamauchi, Hajime; Yoshida, Masashi; Mori, Masayuki; Hida, Yamato; Tran, Ha Nam; Ohkura, Masamichi; Abe, Manabu; Akimoto, Yoshihiro; Nakamichi, Yoko; Nishiwaki, Chiyono; Kawakami, Hayato; Hara, Kazuo; Sakimura, Kenji; Nagamatsu, Shinya; Mori, Yasuo; Nakai, Junichi; Kakei, Masafumi; Ohtsuka, Toshihisa

doi:10.1016/j.celrep.2018.12.106

Cited by 33 publications

(57 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Single-cell impairments in insulin exocytosis from human T2D b-cells (11, 32) may result from reduced glucose-dependent granule docking (12) and disrupted localization of granule fusion to sites of Ca 2+ entry (26-28). Previous studies have suggested both directional control of insulin release towards the vasculature in situ (13)(14)(15) and the existence of repetitive release sites (18)(19)(20)(21)(22). Focal adhesion activation may contribute to this (52), resulting from ECM-dependent interactions that drive cell polarity in situ (17).…”

Section: Discussionmentioning

confidence: 99%

“…While b-cells lack ultra-structurally identifiable active zones, glucose-stimulation in situ triggers fusion events that are progressively localized to preferential release sites (13). These appear directed towards the islet vasculature (13)(14)(15) and are regulated by extracellular matrix (ECM) interactions with integrin receptors (16), which likely play an important role defining the polarity which defines b-cell organization in situ (17). Fusion events in vitro also appear nonrandom in insulinoma cells and rodent b-cells, where exocytosis may occur at sites of recently fused vesicles (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

Githaka

Dai

et al. 2019

Preprint

View full text Add to dashboard Cite

Fu et al.Spatial organization of exocytosis in human b-cells 2 SUMMARY Impaired insulin secretion in type 2 diabetes (T2D) is linked to reduced insulin granule docking, disorganization of the exocytotic site, and an impaired glucose-dependent facilitation of insulin exocytosis. We show in b-cells from 80 human donors that the glucose-dependent amplification of exocytosis is disrupted in T2D. Spatial analyses of granule fusion, visualized by total internal reflection fluorescence (TIRF) microscopy in 24 of these donors, demonstrate that these are non-random across the surface of b-cells from donors with no diabetes (ND). The compartmentalization of events occurs within regions defined by concurrent or recent membrane-resident secretory granules. This organization, and the number of membraneassociated granules, is glucose-dependent and notably impaired in T2D b-cells. Mechanistically, multi-channel Kv2.1 clusters contribute to maintaining the density of membrane-resident granules and the number of fusion 'hotspots', while SUMOylation sites at the channel N-(K145) and C-terminus (K470) determine the relative proportion of fusion events occurring within these regions. Thus, a glucose-dependent compartmentalization of fusion, regulated in part by a structural role for Kv2.1, is disrupted in b-cells from donors with type 2 diabetes.Abstract:

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

Githaka

Dai

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…An immunoblotting analysis detected a single band of ~400 kDa in a primary culture of rat hippocampal neurons (Pinto et al, ). This antibody has also been used in immunoblotting and immunohistochemistry (Chen, Mizushige, & Nishimune, ; Ohara‐Imaizumi et al, ; Pérez de Sevilla Müller et al, 2015; Schoen et al, ).…”

Section: Methodsmentioning

confidence: 99%

Vesicular nucleotide transporter‐immunoreactive type I cells associated with P2X3‐immunoreactive nerve endings in the rat carotid body

Yokoyama

Yamamoto

Hirakawa

et al. 2019

J of Comparative Neurology

View full text Add to dashboard Cite

show abstract

“…4C). This was likely because CAST family protein ELKS, which also regulates the Ca 2+ -triggered exocytosis www.nature.com/scientificreports www.nature.com/scientificreports/ at pancreatic β cells 23,46 , could facilitate OXT release from the posterior pituitary in CAST KO mice (Fig. 4A).…”

Section: Scientific Reports |mentioning

confidence: 99%

Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams

Hagiwara

Sugiyama

Ohtsuka

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Although sociological studies affirm the importance of parental care in the survival of offspring, maltreatment-including child neglect-remains prevalent in many countries. While child neglect is well known to affect child development, the causes of maternal neglect are poorly understood. Here, we found that female mice with a deletion mutation of CAST (a presynaptic release-machinery protein) showed significantly reduced weaning rate when primiparous and a recovered rate when multiparous. Indeed, when nurturing, primiparous and nulliparous CAST knock out (KO) mice exhibited less crouching time than control mice and moved greater distances. contrary to expectations, plasma oxytocin (OXT) was not significantly reduced in CAST KO mice even though terminals of magnocellular neurons in the posterior pituitary expressed CAST. We further found that compared with control mice, CAST KO mice drank significantly less water when nurturing and had a greater preference for sucrose during pregnancy. We suggest that deficiency in presynaptic release-machinery protein impairs the facilitation of some maternal behaviours, which can be compensated for by experience and learning.Parental care is essential for the survival of mammalian offspring and influences their adult lives mentally and physically. Naturally, both parents have responsibilities from nest building to feeding, but because they lactate, the primary responsibility for parental care falls to mothers 1 . As nursing is essential for mammalian survival, the basic neural mechanisms underlying maternal care are likely conserved throughout the mammalian evolutionary tree. Therefore, studying these neural mechanisms in non-human mammalian models such as gene-transgenic mice 2 can help us understand human maternal care and prevent neglect. In rodents, maternal behaviours such as nest building, gathering pups together in the nest, keeping them warm, and nursing are critical for pup survival.Complex maternal behaviours require highly motivated and flexible neural systems and have frequently been associated the neuropeptide oxytocin (OXT), which is secreted in both the periphery and the brain 2-5 . Indeed, considerable evidence indicates that OXT promotes maternal behaviour, while OXT deficiency (OXT KO in rats) results in impaired milk ejection without obvious defects in parturition 3 . Similarly, a null mutation of the OXT receptor in mice led to defects in lactation and maternal behaviour 6,7 . Additionally, mice deficient in CD38 (a transmembrane glycoprotein with ADP-ribosyl cyclase activity) also showed defects in maternal behaviour correlating with the reduction of plasma OXT levels 8 . Therefore, OXT and its receptor system are essential for the regulation of maternal behaviour. However, OXT is just one of the many critical players; complex maternal behaviours are also regulated by other neuromodulators including dopamine, serotonin, norepinephrine, and corticotropin-releasing factor, which have been associated with maternal motivation and stress-induced anti-maternal be...

show abstract

ELKS/Voltage-Dependent Ca2+ Channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β Cells

Abstract: Highlights d ELKS regulates L-type VDCC opening and first-phase insulin secretion from b cells d ELKS interacts with the VDCC-b subunits d ELKS localizes at the vascular side of the b cell plasma membrane in islets d ELKS/VDCC-b subunit module controls polarized Ca 2+ influx in b cells

Cited by 33 publications

References 69 publications

A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

Vesicular nucleotide transporter‐immunoreactive type I cells associated with P2X3‐immunoreactive nerve endings in the rat carotid body

Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams

Contact Info

Product

Resources

About