Carboxypeptidase E is required for normal synaptic transmission from photoreceptors to the inner retina

Zhu, Xuemei; Wu, Kaijin; Rife, Lawrence; Cawley, Niamh X.; Brown, B. M.; Adams, Tiffany L.; Teofilo, Karen; Lillo, Concepción; Williams, David S.; Loh, Y. Peng; Craft, Cheryl M.

doi:10.1111/j.1471-4159.2005.03460.x

Cited by 31 publications

(31 citation statements)

References 42 publications

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“…We initially characterized the CPE KO mouse with respect to its most obvious phenotypes: obesity, diabetes, and infertility (7). Other studies on CPE KO mice have shown defective secretion of mature brain-derived neurotrophic factor (BDNF) in the hippocampus (26), defective secretion of glutamate in the retina (40), specific neuronal degeneration in the CA3 region of the hippocampus (36), and defective dendritic pruning and spine formation of layer V cortical neurons (6,35). Thus CPE appears to play a role, either directly or indirectly, in many processes both inside and outside the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

Cawley¹,

Yanik²,

Woronowicz³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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YP.Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am J Physiol Endocrinol Metab 299: E189 -E197, 2010. First published May 11, 2010; doi:10.1152/ajpendo.00516.2009.-Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme, and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin-releasing hormone, and cocaineand amphetamine-regulated transcript (CART). Here, we show that CPE KO mice, an obese animal model, have low bone mineral density (BMD) accompanied by elevated plasma CTX-1 (carboxy-terminal collagen crosslinks), and osteocalcin, indicators of increased bone turnover. Receptor activator for NF-B ligand (RANKL) expression was elevated ϳ2-fold relative to osteoprotegerin in the femur of KO animals, suggesting increased osteoclastic activity in the KO mice. In the hypothalamus, mature CART, a peptide involved in eating behavior and implicated in bone metabolism, was undetectable. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling, since MC4R KO and NPY KO mice have increased BMD. However, reduction of ␣-MSH, the primary ligand of MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the singlegene KO phenotypes. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis. CARBOXYPEPTIDASE E (CPE) is a processing enzyme that is highly expressed in endocrine cells and peptidergic neurons (17,19). It functions to cleave carboxy-terminally extended lysine and arginine residues from peptide hormone and neuropeptide intermediates to form bioactive peptides in the regulated secretory pathway (RSP). In addition to its enzymatic function, CPE has been shown to facilitate trafficking of several prohormones into the granules of the RSP (10, 26). Recently, live-cell imaging and coimmunoprecipitation studies demonstrated a role for its cytoplasmic carboxyl terminus in the transport of peptidergic vesicles via interaction with dynactin, an anterograde microtubule-based motor protein complex (27,28). The involvement of CPE in multiple cellular functions would suggest that deficiencies in CPE would lead to many pathologies. Indeed, the CPE knockout (KO) mouse exhibits multiple endocrinopathies leading to diabetes, infertility, and obesity (7).During our initial characterization of the phenotype of the CPE KO mice, which included physical and biochemical measurements as well as behavioral tests (7), we observed unexpectedly that bone mineral density (BMD) measurements of the CPE KO mice were lower th...

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Section: Discussionmentioning

confidence: 99%

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

Cawley¹,

Yanik²,

Woronowicz³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Studies in vertebrates and invertebrates have demonstrated that CPE is required for neurotransmission. [84][85][86] Cell biological studies in CPE-knockout mice demonstrated that loss of CPE leads to significant reductions of synaptic vesicles docked at active zones. This phenotype, which is similar to that of synapsin knockouts, was not the result of decreased synaptic protein levels or of defects in synaptic vesicle biogenesis.…”

Section: F-actin Is Required For Proper Development Of the Presynaptimentioning

confidence: 99%

The actin cytoskeleton in presynaptic assembly

Nelson

Stavoe

Colón-Ramos

2013

Cell Adhesion & Migration

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“…[15][16][17] The Nrl Ϫ/Ϫ and Nrl Ϫ/Ϫ Grk1 Ϫ/Ϫ mice maintained in total darkness, ambient (ϳ5 lux) cyclic light, or bright (ϳ8000 lux) constant light were recorded at 1, 3, 5, 7, and 9 months of age. At least 10 mice were recorded for each genotype at each age.…”

Section: Electroretinographymentioning

confidence: 99%

Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in theNrl^−/−Grk1^−/−Mouse Retina

Yetemian

Brown

Craft

2010

Invest. Ophthalmol. Vis. Sci.

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These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl(-/-) background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl(-/-)Grk1(-/-) mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis.

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Carboxypeptidase E is required for normal synaptic transmission from photoreceptors to the inner retina

Cited by 31 publications

References 42 publications

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

The actin cytoskeleton in presynaptic assembly

Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in theNrl^−/−Grk1^−/−Mouse Retina

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Carboxypeptidase E is required for normal synaptic transmission from photoreceptors to the inner retina

Cited by 31 publications

References 42 publications

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density

The actin cytoskeleton in presynaptic assembly

Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in theNrl−/−Grk1−/−Mouse Retina

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Neovascularization, Enhanced Inflammatory Response, and Age-Related Cone Dystrophy in theNrl^−/−Grk1^−/−Mouse Retina