Calcium channels, transporters and exchangers in placenta: a review

doi:10.1016/j.ceca.2004.06.010

Cell Calcium

Volume 37, Issue 1, January 2005, Pages 1-8

https://doi.org/10.1016/j.ceca.2004.06.010 Get rights and content

Abstract

Calcium (Ca²⁺) entry in cells is crucial for development and physiology of virtually all cell types. It acts as an intracellular (second) messenger to regulate a diverse array of cellular functions, from cell division and differentiation to cell death. Among candidates for Ca²⁺ entry in cells are—voltage-dependant Ca²⁺ channels (VDCCs), transient receptor potential (TRP)-related Ca²⁺ channels and store-operated Ca²⁺ (SOC) channels. Plasma membrane Ca²⁺-ATPases (PMCA) and Na⁺/Ca²⁺ exchanger (NCX) are mainly responsible for Ca²⁺ extrusion. These different Ca²⁺channels/transporters and exchangers exhibit specific distribution and physiological properties. During pregnancy, the syncytiotrophoblast layer of the human placenta transfers as much as 30 g of Ca²⁺ from the mother to the fetus, especially in late gestation where Ca²⁺ transport through different channels must increase in response to the demands of accelerating bone mineralization of the fetus. The identification and characterization of the different Ca²⁺ channels/transporters and exchangers on the brush-border membrane (BBM) facing the maternal circulation, and the basal plasma membrane (BPM) facing the fetal circulation; placental membrane of the syncytiotrophoblasts have been the focus of numerous studies. This review discusses current views in this field regarding localization and functions during transcellular Ca²⁺ entry and extrusion from cells particularly in the placenta.

Introduction

Calcium (Ca²⁺) is the fifth most abundant element in the earth's crust and the most abundant cation in the human body [1]. The ionic form of Ca²⁺ serves as a universal intracellular messenger to modulate many processes such as neurotransmission, enzyme and hormone secretion as well as many biological processes, e.g. cell cycle regulation and programmed cell death [2], [3]. Two pathways are responsible for Ca²⁺ entry into the body [1]. In the paracellular pathway, Ca²⁺enters via tight junctions located between epithelial cells. The transepithelial Ca²⁺ active transport proceeds through a well-controlled sequence of events consisting of apical Ca²⁺ entry involving, channels such as voltage dependent Ca²⁺ entry (VDCCs) and members of the transient receptor potential (TRP) gene family, specifically TRPV5 and TRPV6 (or CaT1 and ECaC1, see below), and then, cytosolic diffusion of Ca²⁺ bound to calbindins (CaBPs) and finally, basolateral extrusion of Ca²⁺ through plasma membrane Ca²⁺-ATPase (PMCA) and to a lesser extent by Na⁺/Ca²⁺ exchanger (NCX) [4], [5]. Similar mechanisms of transcellular Ca²⁺ transport exist in renal distal tubules and syncytiotrophoblasts of the placenta [1].

The syncytiotrophoblasts are polynucleate structures characterized by the presence of a brush border membrane (BBM) facing the maternal circulation, and a basal plasma membrane (BPM) facing the fetal circulation. This functional unit originates from the differentiation of cytotrophoblasts (predominant cells during the 1st trimester of pregnancy) into syncytiotrophoblasts (predominant cells during the 3rd trimester) [6]. The syncytiotrophoblasts actively transport ∼80% of Ca²⁺ from maternal to fetal circulation where it is needed for fetal skeleton growth, especially during the third trimester of pregnancy [7], [8]. Thus, the maintenance of low intracellular concentrations of Ca²⁺ is essential both for cell survival and for the divalent metal to function as a second messenger [9]. A wide array of mechanisms participates in attaining such a homeostatic condition. Mechanisms of Ca²⁺ entry and extraction via channels/transporters and exchangers are among some strategies involved in Ca²⁺ regulation in different tissues including the placenta.

Therefore, this review focuses on the tissue distribution and functional properties of channels, transporters, and exchangers in cells with a special emphasis on the placenta. Whenever possible, attempts have been made to interrelate information to provide the most likely explanation for phenomena that are currently only partially understood.

Section snippets

VDCCs channels

VDCCs provide a rapid voltage dependent Ca²⁺ entry of extracellular Ca²⁺ into the cytoplasm [10] in many cell types including nerves, muscle and endocrine cells [11]. The first possible existence of VDCCs channels was reported in 1975 by Hagiwara et al. [12]. Since then, noticeable advances have been made regarding the electrophysiology and molecular biology of VDCCs. Currently, two major classes of VDCCs have been categorized. The first category consists of high voltage-activated (HVA) Ca²⁺

Ca²⁺ channels related to the TRP family

Transcellular Ca²⁺ transport, which is important in the intestine, kidney and placenta, is carried out partly by the transient receptor potential (TRP) channel superfamily. It is a large class of channel subunits united by a modestly similar primary structure and permeable to monovalent cations and Ca²⁺ ions [41]. This family has three subfamilies: TRPC (canonical), TRPM (Melastatin) and TRPV (vanilloid) [42]. The TRPV subfamily includes TRPV5 and TRPV6 that are the highly Ca²⁺-selective

SOC channels

A major function of SOC channels is in regulating intracellular Ca²⁺ [59]. Thus, the emptying of intracellular Ca²⁺ stores generates a putative signal that induces the opening of SOC channels at the level of the cell membrane and the influx of Ca²⁺ into cells, known as capacitative Ca²⁺ entry (CCE) [3], [60], [61]. To distinguish this from other Ca²⁺ entry channels, the term of Ca²⁺ release activated Ca²⁺ currents (ICRAC) has been used to refer to the current flowing through CRAC channels [62],

Conclusion

Placental Ca²⁺ transport and regulation is a highly complex and largely ill understood phenomenon. To date, much of our knowledge is fragmentary. Studies on the localization, function and regulation of the highly Ca²⁺-selective channels CaT1 and CaT2 have indicated that they are major players in the apical entry of transcellular Ca²⁺ for intestine, kidneys and placenta. Clinically, these channels may possibly be involved in multifactorial pathogenesis of disorders including idiopathic

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Calcium channels, transporters and exchangers in placenta: a review

Abstract

Introduction

Section snippets

VDCCs channels

Ca2+ channels related to the TRP family

SOC channels

Conclusion

Kidney Int.

J. Biol. Chem.

FEBS Lett.

Neuron

Trend in Neural Science

Kidney Int.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta.

Placenta

Biol. Chem.

Trends Neurosci.

Genomics

Biochim. Biophys. Acta.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Genomics

Arch. Med. Res.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Placenta

Biochem. Biophys. Res. Commun.

Genomics

J. Biol. Chem.

J. Biol. Chem.

Apical entry channels in Ca2+ transporting epithelia

New Physiol. Sci.

Intracellular Ca2+. Replenishing the stores

Nature

Capacitative Ca2+ entry

Biochem. J.

Ca2+ handling by the mammalian kidney

J. Exp. Biol.

Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae

Endocrinology

Vitamin D metabolism in preterm infants

Biol. Neonate

Votage-gated Ca2+ Channels

Molecular and functional characterization of a family of rat brain T-type Ca2+ channels

J. Biol. Chem.

Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of the starfish

J. Gen. Physiol.

Ca2+ channels-basic aspects of their structure, function and gene encoding; anesthetic action on the channels, a review

Can. J. Anaesth.

Structure, function and expression of Ca2+ channels

Nippon Rinsho.

Three types of neuronal Ca2+ channel with different Ca2+agonist sensitivity

Nature

Ca2+ channel modulation by neurotransmitters, enzymes and drugs

Nature

Subunit structure of dihydropyridine sensitive Ca2+ channel from skeletal muscle

Proc Natl. Acad. Sci. USA

Stimulation of intracellular calcium concentration by adenosine triphosphate and uridine 5’-triphosphate in human term placental cells: evidence for purinergic receptors

J. Clin. Endocrinol. Metab.

Identification of L-type Ca2+ channels associated with kappa opioid receptors in human placenta

J. Mol. Neurosci.

Ca²⁺ channels related to the TRP family

Apical entry channels in Ca²⁺ transporting epithelia

Intracellular Ca²⁺. Replenishing the stores

Capacitative Ca²⁺ entry

Ca²⁺ handling by the mammalian kidney

Votage-gated Ca²⁺ Channels

Molecular and functional characterization of a family of rat brain T-type Ca²⁺ channels

Ca²⁺ channels-basic aspects of their structure, function and gene encoding; anesthetic action on the channels, a review

Structure, function and expression of Ca²⁺ channels

Three types of neuronal Ca²⁺ channel with different Ca²⁺agonist sensitivity

Ca²⁺ channel modulation by neurotransmitters, enzymes and drugs

Subunit structure of dihydropyridine sensitive Ca²⁺ channel from skeletal muscle

Identification of L-type Ca²⁺ channels associated with kappa opioid receptors in human placenta