Peptidylglycine α-amidating monooxygenase is required for atrial secretory granule formation

Back, Nathan; Luxmi, Raj; Powers, Kathryn G.; Mains, Richard E.; Eipper, Betty A.

doi:10.1073/pnas.2004410117

Cited by 25 publications

(57 citation statements)

References 82 publications

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“…Its monooxygenase activity relies on the availability of adequate levels of molecular oxygen, copper and ascorbic acid, while its cytosolic domain controls trafficking through the secretory and endocytic pathways. In addition to its enzymatic roles, PAM plays an essential, non‐catalytic role in the assembly of the atrial myocyte granules that contain natriuretic peptides 14,15 . Based on our earlier studies of Pam +/− mice 8,9,11,59 and Pam Emx1‐cKO/cKO mice, 14 we used Pam Emx1‐cKO/cKO mice to disturb the excitatory/inhibitory balance essential to amygdalar and hippocampal function.…”

Section: Discussionmentioning

confidence: 99%

“… 61,62 Atrial myocytes unable to express PAM lack the dense granules that normally store proANP, and circulating ANP is undetectable 14 . The ability of Pam Myh6‐cKO/cKO atrial myocytes to store proANP is restored by virally‐mediated expression of active or catalytically inactive PAM 15 …”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, as observed in Pam +/− mice, Pam Myh6‐cKO/cKO mice exhibited increased anxiety‐like behavior 14 . The near‐total loss of atrial secretory granules and low serum levels of atrial natriuretic peptide (ANP) in Pam Myh6‐cKO/cKO mice suggest that anxiety‐like behavior is altered through a very different pathway 14,15 . Central and peripheral administration of ANP is anxiolytic, and circulating ANP levels have a strong negative correlation with anxiety in human cardiac and psychiatric patients 25,26 …”

Section: Introductionmentioning

confidence: 97%

“…Neuropeptides play a key role in modulating excitatory/inhibitory balance 12,13 . With the availability of viable mice with both alleles of Pam floxed, the biochemical, physiological and behavioral consequences of completely ablating PAM expression in excitatory forebrain neurons using mice expressing Cre‐recombinase under control of the Emx1 promoter was examined 14,15 . Unlike Pam +/− mice, Pam Emx1‐cKO/cKO mice exhibited decreased anxiety‐like behavior and increased cold tolerance 14 .…”

Section: Introductionmentioning

confidence: 99%

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Cell‐type specific knockout of peptidylglycine α‐amidating monooxygenase reveals specific behavioral roles in excitatory forebrain neurons and cardiomyocytes

Powers

Eipper

et al. 2020

Genes Brain and Behavior

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Neuropeptides and peptide hormones play a crucial role in integrating the many factors that affect physiologic and cognitive processes. The potency of many of these peptides requires an amidated amino acid at the C‐terminus; a single enzyme, peptidylglycine α‐amidating monooxygenase (PAM), catalyzes this modification. Anxiety‐like behavior is known to be altered in mice with a single functional Pam allele (Pam+/−) and in mice unable to express Pam in excitatory forebrain neurons (PamEmx1‐cKO/cKO) or in cardiomyocytes (PamMyh6‐cKO/cKO). Examination of PAM‐positive and glutamic acid decarboxylase 67 (GAD)‐positive cells in the amygdala of PamEmx1‐cKO/cKO mice demonstrated the absence of PAM in pyramidal neurons and its continued presence in GAD‐positive interneurons, suggestive of altered excitatory/inhibitory balance. Additional behavioral tests were used to search for functional alterations in these cell‐type specific knockout mice. PamEmx1‐cKO/cKO mice exhibited a less focused search pattern for the Barnes Maze escape hole than control or PamMyh6‐cKO/cKO mice. While wildtype mice favor interacting with novel objects as opposed to familiar objects, both PamEmx1‐cKO/cKO and PamMyh6‐cKO/cKO mice exhibited significantly less interest in the novel object. Since PAM levels in the central nervous system of PamMyh6‐cKO/cKO mice are unaltered, the behavioral effect observed in these mice may reflect their inability to produce atrial granules and the resulting reduction in serum levels of atrial natriuretic peptide. In the sociability test, male mice of all three genotypes spent more time with same‐sex stranger mice; while control females showed no preference for stranger mice, female PamEmx1‐cKO/cKO mice showed preference for same‐sex stranger mice in all trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cell‐type specific knockout of peptidylglycine α‐amidating monooxygenase reveals specific behavioral roles in excitatory forebrain neurons and cardiomyocytes

Powers

Eipper

et al. 2020

Genes Brain and Behavior

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“…This article is protected by copyright. All rights reserved specific Myh6-promoter, we generated mice unable to express PAM in cardiomyocytes (Pam Myh6-cKO/cKO ) [15,16]. Strikingly, the granules characteristic of atrial myocytes were not present in Pam Myh6-cKO/cKO mice.…”

Section: Accepted Articlementioning

confidence: 99%

PAM: diverse roles in neuroendocrine cells, cardiomyocytes, and green algae

2021

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Our understanding of the ways in which peptides are used for communication in the nervous and endocrine systems began with the identification of oxytocin, vasopressin and insulin, each of which is stored in electron dense granules, ready for release in response to an appropriate stimulus. For each of these peptides, entry of its newly synthesized precursor into the endoplasmic reticulum lumen is followed by transport through the secretory pathway, exposing the precursor to a sequence of environments and enzymes that produce the bioactive products stored in mature granules. A final step in the biosynthesis of many peptides is C-terminal amidation by Peptidylglycine -Amidating Monooxygenase (PAM), an ascorbate-and copper-dependent membrane enzyme that enters secretory granules along with its soluble substrates. Biochemical and cell biological studies elucidated the highly conserved mechanism for amidated peptide production and raised many questions about PAM trafficking and the effects of PAM on cytoskeletal organization and gene expression. Phylogenetic studies and the discovery of active PAM in the ciliary membranes of Chlamydomonas reinhardtii, a green alga lacking secretory granules, suggested that a PAM-like enzyme was present in the last eukaryotic common ancestor. While the catalytic features of human and C. reinhardtii PAM are strikingly similar, the trafficking of PAM in C. reinhardtii and neuroendocrine cells and secretion of its amidated products differ. A comparison of PAM function in neuroendocrine cells, atrial myocytes and C. reinhardtii reveals multiple ways in which altered trafficking allows PAM to accomplish different tasks in different species and cell-types.This article is protected by copyright. All rights reserved encoding their precursors revealed the importance of post-translational processing in the production of bioactive peptides [5,6]. With the identification of COOH-terminal amidation as a critical step in the synthesis of peptides like vasopressin, oxytocin, neuropeptide Y, cholecystokinin and -melanocyte stimulating hormone, searches for an amidating enzyme began [7][8][9]. The sequencing of cDNAs encoding the prepropeptides for amidated peptides indicated that each amidated peptide was produced from a precursor with a COOH-terminal glycine.Using bovine and rodent pituitaries, a soluble monooxygenase that converted peptidylglycine substrates into amidated products, peptidylglycine -hydroxylating monooxygenase (PHM; E.C. 1.14.17.3), was identified and shown to require copper and ascorbic acid (Fig. 1A) [9]. The purification of soluble, ~40 kDa PHM led to the expression cloning of a cDNA that encoded a 110 kDa Type I integral membrane protein that included an NH 2terminal signal sequence followed by PHM (Fig. 1A) [10]. With a cDNA in hand, it quickly became apparent that the luminal region of this membrane protein included two catalytic activities, PHM and peptidyl-hydroxyglycine -amidating lyase (PAL; E.C. 4.3.2.5) (Fig. 1A) [7,11]. Under the slightly acidic conditions encountere...

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Multiple roles for peptidylglycine α‐amidating monooxygenase in the response to hypoxia

Rao

Eipper

Mains

2021

Journal Cellular Physiology

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Peptidylglycine α-amidating monooxygenase is required for atrial secretory granule formation

Cited by 25 publications

References 82 publications

Cell‐type specific knockout of peptidylglycine α‐amidating monooxygenase reveals specific behavioral roles in excitatory forebrain neurons and cardiomyocytes

Cell‐type specific knockout of peptidylglycine α‐amidating monooxygenase reveals specific behavioral roles in excitatory forebrain neurons and cardiomyocytes

PAM: diverse roles in neuroendocrine cells, cardiomyocytes, and green algae

Multiple roles for peptidylglycine α‐amidating monooxygenase in the response to hypoxia

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