Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals

James F Collins

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128021682
• eBook ISBN: 9780128023761
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals is a unique reference that provides a complete overview of the non-vitamin micronutrients, including calcium, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, sodium, and zinc. In addition, the book covers the nutritional and toxicological properties of nonessential minerals chromium, fluoride and boron, and silicon and vanadium, as well as ultra-trace minerals and those with no established dietary requirement for humans. Users will find in-depth chapters on each essential mineral and mineral metabolism, along with discussions of dietary recommendations in the United States and around the world. - Presents the only scientific reference to cover all of the nutritionally relevant essential major and trace minerals - Provides a broad introductory chapter on each mineral to give readers valuable background and context - Clarifies the cellular and molecular aspects of each mineral and its genetic and genomic aspects - Includes coverage of all nutritionally relevant minerals—essential major trace minerals and ultra-trace minerals - Underscores the important interactions between minerals so readers learn how metabolism of one mineral influences another

Part I

Calcium

Outline

Chapter 1. Calcium-Sensing Receptor Polymorphisms and Human Disease

Chapter 2. Molecular Aspects of the Calcium-Sensing Receptor and Calcium Homeostasis

Chapter 3. New Developments in Our Understanding of the Regulation of Calcium Homeostasis by Vitamin D

Chapter 4. Calcium in Obesity and Related Diseases: The Calcium-Sensing Receptor as a Novel Mediator

Chapter 5. Calcium: Basic Nutritional Aspects

Chapter 6. Molecular Aspects of Calcium and Bone Mineralization

Chapter 1

Calcium-Sensing Receptor Polymorphisms and Human Disease

Giuseppe Vezzoli¹, Laura Soldati², and Stefano Mora^{1 1}IRCCS San Raffaele Scientific Institute, Milan, Italy ²Università degli Studi of Milan, Milan, Italy

Abstract

The calcium-sensing receptor (CaSR) is a plasma membrane protein that senses calcium in the extracellular fluid. Cloned from bovine parathyroid cells in 1993, CaSR is mainly expressed in the parathyroid glands and renal distal tubules, and it enables these tissues to regulate parathyroid hormone secretion and calcium excretion, respectively, in response to changes in serum calcium. CaSR is also crucial for normal growth plate development and bone remodeling. Therefore CaSR is a key regulator of calcium homeostasis. Moreover, CaSR polymorphisms have been associated with serum calcium concentration and urine calcium excretion in humans. Polymorphisms decreasing CaSR expression in renal tubular cells may increase risk for developing calcium oxalate kidney stones. CaSR gene polymorphisms may modify the phenotype of healthy subjects and patients with primary and secondary hyperparathyroidism, and it may allow identification of individuals prone to developing kidney stones.

Keywords

Calcimimetics; Calcium-sensing receptor; Genetic polymorphisms; Hypercalcemia; Hyperparathyroidism; Hypocalcemia; Kidney stone disease

Introduction

Circulating calcium ions can directly modulate cell activity in humans by means of a plasma membrane receptor that is sensitive to extracellular calcium, the calcium-sensing receptor (CaSR). CaSR was firstly cloned from bovine parathyroid cells in 1993 (Brown et al., 1992) and then in human parathyroid cells and renal tubular cells (Aida et al., 1995; Garrett et al., 1995). CaSR is a 1078-amino–acid protein that belongs to the third class of G-protein-coupled receptor (GPCR) family. It is expressed as a disulfide-linked homodimer in caveolin-rich areas of the plasma membrane, although it may also form heterodimers with other members of the GPCR family (Kifor et al., 1998). As an environmental sensor, CaSR elicits the paracrine or autocrine adaptive responses of human cells to changes in local or serum calcium concentrations. This adaptive response is fundamental for the physiological effect of parathyroid and kidney cells in human calcium homeostasis. The parathyroid glands and renal distal tubules are the tissues with the highest expression of CaSR, and its presence enables them to regulate calcium excretion and parathyroid hormone (PTH) secretion in response to serum calcium changes (Fig. 1.1). CaSR stimulation by the increase of serum calcium is followed by the inhibition of calcium reabsorption in the renal tubules and PTH secretion to restore normal serum calcium levels (Riccardi and Brown, 2010; Riccardi and Kemp, 2012). CaSR was also shown to be essential for osteoblast-mediated bone remodeling (Dvorak et al., 2004). Therefore CaSR is a key factor in calcium homeostasis (Riccardi and Kemp, 2012).

The CaSR molecule includes a large bilobed Venus-flytrap–like extracellular domain of 612 amino acids, a seven-membrane–spanning domain of 250 amino acids, and a C-terminal intracellular domain of 216 amino acids (Riccardi and Kemp, 2012). Calcium binding to the negatively charged residues in the pocket of the CaSR extracellular domain induces a conformational change of the CaSR molecule that causes the transmembrane and intracellular domains to activate intracellular signaling. Calcium ions are the main CaSR agonists, but CaSR also responds to other divalent (Ba, Cd, Co, Mg) and trivalent (Gd, La) cations and to polycationic compounds such as polyamines, aminoglycosides (neomycin, gentamycin), and polypeptides (poly-L-arginine, β-amyloid) (Riccardi and Kemp, 2012). The signaling cascade induced by CaSR activation is tissue specific and mediated by G-proteins (Fig. 1.2) (Magno et al., 2011). However, CaSR has also been identified in many organs not directly involved in calcium homeostasis and is now considered as ubiquitously expressed in mammalian cells. It has been implicated in insulin secretion, adipocyte metabolism, smooth muscle cell activity, and gastric function (Table 1.1), although its effects in these tissues is not as crucial as that in calcium-regulating organs (Riccardi and Kemp, 2012).

The human CaSR gene (3q13.3–21) spans 103 kb and comprises eight exons with two promoters, P1 and P2, having unknown functional differences (Fig. 1.3) (Canaff and Hendy, 2002). Loss-of-function mutations cause familial hypocalciuric hypercalcemia (FHH; OMIM #145980) in heterozygous patients and severe neonatal hyperparathyroidism (SNH; OMIM #239200) in homozygous patients (Hofer and Brown, 2003; Pearce et al., 1995). In these patients, CaSR cannot inhibit PTH production and renal tubular calcium reabsorption appropriately and patient phenotype is characterized by hypercalcemia and low calcium excretion. Serum PTH and calcium are slightly or moderately high in FHH, but severely high in SNH. SNH patients also develop bone demineralization and failure to thrive in the first 6 months of life. Mutations of two other genes, GNA11 (19p13) and AP2S1 (19q13), may also cause FHH. Gain-of-function mutations of CaSR cause autosomal dominant hypercalcemia (ADH; OMIM #601198), a disorder characterized by high urinary calcium excretion and inappropriately low serum PTH and hypocalcemia. ADH in patients with highly activating mutations is associated with Bartter syndrome type 5 because of a urinary sodium and potassium leak resulting in renal hypokalemia (Vezzoli et al., 2006).

Figure 1.1 Renal and parathyroid response to increases in serum calcium concentrations. Calcium-sensing receptor (CaSR) is sensitive to tubular fluid calcium in the proximal tubule and in the collecting duct whereas it responds to serum calcium in the ascending limb and the cortical convoluted tubule.

Figure 1.2 Calcium ions bind to the negatively charged pocket of the calcium-sensing receptor (CaSR) extracellular domain and activate different signaling cascades mediated by G-proteins. Various protein-binding partners of the CaSR’s C-terminal region have been recognized, including filamin, potassium channels, dorfin, and β-arrestin.

CaSR activity may be modified by genetic polymorphisms (Table 1.2). Two nonsynonymous polymorphisms of the intracellular domain, rs1801725 and rs1402636, have a significant frequency in the general population and are associated with specific benign phenotypes. In addition, polymorphisms of noncoding regions of CaSR have been associated with specific phenotypes; among them, the rs6776158 polymorphism of promoter 1 may have particular relevance in human disorders.

Table 1.1

Functions of Different Cells Influenced by Extracellular Calcium Ions and Calcium-Sensing Receptor Activities (Riccardi and Kemp, 2012).

Organ	Effect	Related Human Disorders or Phenotype
Parathyroid glands	Inhibition of parathyroid hormone secretion	Autosomal-dominant hypocalcemia, familial hypocalciur...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Series Preface
• Part I. Calcium
• Part II. Copper
• Part III. Iodine
• Part IV. Iron
• Part V. Zinc
• Part VI. Magnesium
• Part VII. Manganese
• Part VIII. Molybdenum
• Part IX. Phosphorus
• Part X. Selenium
• Part XI. Electrolytes
• Part XII. Nonessentials
• Index