Role of receptor activity modifying protein-2 (RAMP2) in endocrine physiology of female mice Public Deposited

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  • March 21, 2019
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  • Kadmiel, Mahita
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Receptor activity modifying proteins (RAMPs 1, 2, and 3) are single-pass transmembrane proteins that can regulate the trafficking, ligand-binding, and signaling of several G protein-coupled receptors (GPCRs). For example, biochemical studies have shown that RAMP2 interacts with calcitonin receptor-like receptor (CLR), parathyroid hormone receptor (PTHR1) and calcitonin receptor (CTR). However, the most well-characterized role of RAMP2 is in the regulation of adrenomedullin (AM; gene: Adm) binding to CLR (gene: Calcrl), and previous in vivo work from the Caron laboratory supports this canonical signaling paradigm. Loss of RAMP2 causes embryonic lethality associated with failed lymphatic vascular development, which is a precise phenocopy of the defects seen in Adm-/- and Calcrl-/- mice. However, Ramp2+/- mice survive, and here we present the phenotypic analyses of Ramp2+/- female mice and Ramp2-/- placentas, many of which are distinct from the phenotypes observed in Adm and Calcrl mice. Haploinsufficiency of Ramp2 causes severe subfertility in female mice characterized by intrauterine growth restriction and postnatal lethality. Furthermore, Ramp2+/- female mice exhibit hyperprolactinemia, pituitary gland hyperplasia, precocious mammary gland development, and skeletal abnormalities--phenotypes that are distinct from those observed in Adm+/- and Calcrl+/- mice. In addition, Ramp2-/- placentas have marked defects, including reduced labyrinth size, reduced cellularity and reduced proliferation of labyrinthine trophoblast cells. Interestingly, loss of Ramp2 Pthr1Ramp2Adm and Calcrl animals, considerably extends the biological functions of RAMP2 beyond the canonical AM/CLR signaling pathway and supports an essential role for RAMP2 in PTHR1 signaling. Therefore, these studies provide novel physiological insights and potential pharmacological targets for the future development of RAMP2-based therapies for the treatment of female endocrine disorders.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Molecular Physiology, School of Medicine."
Advisor
  • Caron, Kathleen
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  • Chapel Hill, NC
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  • Open access
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