ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Abstract Biosynthesis of most peptide hormones and neuropeptides requires proteolytic excision of the active peptide from inactive proprotein precursors, an activity carried out by subtilisin-like proprotein convertases (SPCs) in constitutive or regulated secretory pathways. The Drosophila amontillado (amon) gene encodes a homolog of the mammalian PC2 protein, an SPC that functions in the regulated secretory pathway in neuroendocrine tissues. We have identified amon mutants by isolating ethylmethanesulfonate (EMS)-induced lethal and visible mutations that define two complementation groups in the amon interval at 97D1 of the third chromosome. DNA sequencing identified the amon complementation group and the DNA sequence change for each of the nine amon alleles isolated. amon mutants display partial embryonic lethality, are defective in larval growth, and arrest during the first to second instar larval molt. Mutant larvae can be rescued by heat-shock-induced expression of the amon protein. Rescued larvae arrest at the subsequent larval molt, suggesting that amon is also required for the second to third instar larval molt. Our data indicate that the amon proprotein convertase is required during embryogenesis and larval development in Drosophila and support the hypothesis that AMON acts to proteolytically process peptide hormones that regulate hatching, larval growth, and larval ecdysis.

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Expression and processing of mouse proopiomelanocortin in bovine adrenal chromaffin cells. A model system to study tissue-specific prohormone processing

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)92743-2 ◽

1991 ◽

Vol 266 (21) ◽

pp. 13607-13615

Author(s):

B.A. Thorne ◽

O.H. Viveros ◽

G. Thomas

Keyword(s):

Chromaffin Cells ◽

Model System ◽

Adrenal Chromaffin Cells ◽

Tissue Specific ◽

Prohormone Processing ◽

Adrenal Chromaffin

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Vasopressin-vermittelte Wasserrückresorption im Sammelrohr der Niere

BIOspektrum ◽

10.1007/s12268-021-1544-1 ◽

2021 ◽

Vol 27 (2) ◽

pp. 165-167

Author(s):

Sandrine Baltzer ◽

Enno Klussmann

Keyword(s):

Water Balance ◽

Small Molecules ◽

High Throughput ◽

Molecular Mechanisms ◽

Collecting Duct ◽

Water Channel ◽

Water Reabsorption ◽

Balance Disorders ◽

Water Homeostasis ◽

Balance Disorder

AbstractVasopressin-mediated water reabsorption from primary urine in the renal collecting duct is essential for regulating body water homeostasis and depends on the water channel aquaporin-2 (AQP2).Dysregulation of the process can cause water balance disorders. Here, we present cell-based high-throughput screenings to identify proteins and small molecules as tools to elucidate molecular mechanisms underlying the AQP2 control and as potential starting points for the development of water balance disorder drugs.

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Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures

ASN NEURO ◽

10.1177/1759091420979604 ◽

2020 ◽

Vol 12 ◽

pp. 175909142097960

Author(s):

Andrew S. Lapato ◽

Sarah M. Thompson ◽

Karen Parra ◽

Seema K. Tiwari-Woodruff

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Regional Differences ◽

Neuronal Excitability ◽

Demyelinating Disease ◽

Glutamate Uptake ◽

Cx43 Expression ◽

Water Homeostasis ◽

Hippocampal Astrocytes ◽

Multiple Sclerosis Patients

While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamate transporters (EAAT2), in a mouse model of MS with seizures (MS+S). However, astrocytes in MS+S have not been examined. To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MS+S, demyelinated lesion burden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry in postmortem hippocampi from MS & MS+S donors. Lesion burden was comparable in MS & MS+S cohorts, but astrogliosis was elevated in MS+S CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MS+S CA1 & CA3 with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MS+S patients display regional differences in expression of molecules associated with glutamate buffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1 perivascular AQP4 seen in MS+S is analogous to epileptic hippocampi without a history of MS, suggesting convergent pathophysiology. Furthermore, as neuropathology was concentrated in MS+S CA1, future study is warranted to determine the pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.

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