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TRP Channels: Emerging Links Between Ca2+, Kidney and Hypertension

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TRP Channels: Emerging Links Between Ca2+, Kidney and Hypertension Send Orders of Reprints at [email protected] Current Hypertension Reviews, 2012, 8, 181-189 181 TRP Channels: Emerging Links Between Ca2+, Kidney and Hypertension Paolo Menè*, Anna Giuliani, Jacopo Scrivano, Francesca Apponi, Giorgio Punzo and Nicola Pirozzi Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, School of Medicine and Psychology, Rome, Italy Abstract: Cationic channels with variable selectivity for Ca2+, K+, and Na+ are ubiquitous in non-excitable tissues as well as contractile cardiac cells and vascular smooth muscle (VSMC). They are involved in multiple cell functions, including contraction and proliferation of VSMC, key to the regulation of vascular tone and blood pressure. A large superfamily includes at least 28 highly conserved heterotetramer homologues of Drosophila TRP (transient receptor potential) channels. Direct evidence exists for TRPC, TRPV, TRPP gating ion entry in vascular cells, as well as in epithelial cells of kidney and intestine, thus controlling homeostasis and external balance of divalent cations. Mice deficient in TRPV5 display phenotypic defects resembling human idiopathic hypercalciuria and impaired bone mineral density. Polycystin 2, encoded by the PKD2 gene, is an epithelial transmembrane TRPP2 protein, whose mutation is associated with autosomal dominant polycystic kidney disease (ADPKD). TRP ion channels may therefore play a role in the pathogenesis of systemic arterial hypertension, pulmonary hypertension, as well as hypertension complicating renal disease via effects on vascular tone and/or on the electrolyte composition of body fluids. Keywords: Transient Receptor Potential Channels, Store-Operated Ca2+ entry, Pulmonary Hypertension, Arterial Hypertension. INTRODUCTION as photoreceptors in insect retinal cells, and later recognized in a variety of sensing apparatuses [4-7]. These include Regulated permeability of plasma membranes to ions and visual and hearing structures, such as cochlea sensory hair water is key to preserving the internal microenvironment and cells, but are also widely distributed in the cilia of epithelial cell volume in living organisms, resisting to shifts of external cells of various organs [4-7]. Cation influx through these ion concentrations and osmotic/oncotic forces. This is channels often follows activation of a physical or chemical critical for both resting and activated cells, enabling sensor. Selectivity of TRP channels for one divalent cation thorough control of the transmembrane potential, which in such as Ca2+ or Mg2+ vs monovalent Na+ is variable from excitable cell drives electric currents, action potentials, and >100:1 to 1:1, based on isoform structure and tissue type contraction/relaxation. Permeability of the plasma membrane [4-7]. involves a host of channels, water and ion transporters constitutively expressed or translocated to the surface of TRP channels also serve as absorption mechanisms in cells in a highly regulated fashion. Channels or carrier epithelial cells, regulated by transmembrane concentration or proteins not only control a cell’s microenvironment and electrochemical gradients. One such process is “bulk entry”, transmembrane potential, but do also serve for signalling, as in the case of Ca2+ or Mg2+ influx in the duodenum or inasmuch as ion fluxes encode for functional responses in renal tubules. In the kidney, TRPC5 and 6 channels mediate target cells. Vasoconstrictors or vasorelaxant agents, such as epithelial Ca2+ reabsorption in the distal convoluted tubule, peptides or catecholamines, often act by redistributing Ca2+ and hence external Ca2+ balance [8, 9]. Genetically or Mg2+ in intracellular compartments upon activation of the engineered TRPC5-knockout mice exhibit hypercalciuria appropriate receptors [1, 2]. Further levels of signalling may and skeletal defects consistent with altered distal tubular be encoded through frequency and/or amplitude of reabsorption of Ca2+ [8, 9]. This model resembles human oscillatory currents, in turn actuated by cyclic ion gating [3]. idiopathic hypercalciuria. Another epithelial cell mechanism is more of a “fine tuning” nature, in that kidney tubular or Extensive literature has been amassed in the past 10-15 hepatic biliary cells express polycystin 2 (PKD-2), a TRP- years on a large superfamily of ion channels, the so-called type Ca2+ channel in the context of cilia, sensing organelles transient receptor potential (TRP) channels, fairly likely controlling urine or bile flows in the surrounding ubiquitous heterotetrameric polypeptides, initially identified environment [10, 11]. Defects in renal tubular PKD-2- mediated Ca2+ transport, as commonly encountered in autosomic dominant polycystic kidney disese (ADPKD), *Address correspondence to this author at the Dipartimento di Medicina Clinica e Molecolare, Cattedra di Nefrologia, Azienda Ospedaliera may underlie dysregulated epithelial cell proliferation and Sant’Andrea, Via di Grottarossa 1035-1039, 00189 Rome, Italy; thus cyst formation [10,11,12]. Notably, ADPKD is often Tel: +39 (06) 3377-5949; Fax: +39 (06) 3377-5866; associated with arterial hypertension, not necessarily through E-mail: [email protected] 1875-6506/12 $58.00+.00 © 2012 Bentham Science Publishers 182 Current Hypertension Reviews, 2012, Vol. 8, No. 3 Menè et al. the intermediation of chronic renal failure. Obviously, already obtained from studies in spontaneously hypertensive altered Na+ transport and balance through a defective, cystic rats [13-15]. tubular epithelium may be involved in the pathogenesis of the so-called “renoparenchymal” hypertension, often seen in THE TRP SUPERFAMILY OF ION CHANNELS chronic kidney disease even though GFR is preserved. Direct + 2+ Mammalian TRP proteins are an ever-growing list of links between tubular Na and altered Ca handling may cation-permeant homologues of the Drosophila gene also be at play in hypertensive congenital disorders such as transcripts, of which at least 28 members have been so far ADPKD. identified (5-7, 12). The TRP superfamily incorporates 3 Along the same line, the hypothesis has been put forward homologous subfamilies (TRPC, TRPV, and TRPA) and 4 that dysregulated Ca2+ entry through TRP channels in more distantly related subfamilies (TRPM,TRPP, TRPML, vascular smooth muscle cells (VSMC) or endothelial cells and TRPN/NOMPC) (Table 1). TRP proteins further of the pulmonary or systemic microcirculation may be assemble into heterotetramers, combinations of any given implicated in the pathogenesis of pulmonary or arterial isoform in ratios of 1:3, 1:2:1, etc. This implies that hypertension. Data consistent with this model have been electrophysiology and selectivity of a channel are dictated by Table 1. Overview of Known TRP Channel Subfamilies and their Proposed Functions Species Human Murine Insect TRPA 1 thermal (cold) sensing pungent compound sensing thermotaxis TRPC 1 2 sperm acrosome reaction pheromone sensing 3 neurodifferentiation synaptic development 4 vasorelaxation microvascular permeability 5 6 vascular tone regulation 7 TRPV 1 nociception 2 nociception 3 nociception 4 osmo-sensation 5 Ca2+ transport Ca2+ transport, kidney tubules 6 Ca2+ transport Ca2+ transport, duodenum OSM-9 TRPM 1 melanoma tumor suppressor 2 redox-sensing 3 oxidative stress-induced apoptosis 4 cation selective channel 5 taste cells 6 familial hypomagnesemia 7 cell survival, proliferation 8 thermal sensing, tumor marker TRPN TRPL, Drosophila TRP phototransduction TRPP 1 polycystic kidney disease 2 “ 3 “ 5 “ TRPML 1 mucolipin TRP Channels and Hypertension Current Hypertension Reviews, 2012, Vol. 8, No. 3 183 composition of the assembled channels [4, 7]. A typical the list of proposed functions and organs expressing one or classical - or canonic - TRP protein is encoded by a gene more members of the superfamily is continuously expanding. comprised of 24 exons on chromosome 9q-21.12, yielding a The initial view of TRP as signalling receptors has evolved polypeptide chain of 1555 amino acids [4]. The general into that of multifunctional ion channels, which in structure includes 6 transmembrane domains with specialized epithelia (kidney, intestine) may even be adapted cytoplasmic N- and C-termini, incorporating a variety of for massive absorption of electrolytes [9, 23]. putative regulatory sites, including calmodulin / inositol TRP CHANNELS AND PLASMA MEMBRANE Ca2+ (1,4,5)-trisphosphate (InsP ) receptor binding sites, PDZ 3 TRANSPORT binding motifs, phosphorylation sites for protein kinases, ankyrin-like repeats, proline-rich motifs, etc. [5-7, 12-19] The expression “capacitative Ca2+ influx” describes the (Fig. 1). A diacylglycerol (DAG) regulatory site has been ability of various stimuli of the discharge of intracellularly recently described on the N- terminus [18]. As a matter of stored Ca2+ (such as all agents that trigger phospholipase fact, many studies show direct regulation of TRP by DAG as C-γ breakdown of phosphoinositides, releasing InsP3) to in the case of TRPC3 expressed in Chinese hamster ovary initiate a Ca2+ current that refills the stores and accounts 2+ cells, or by related metabolites of phospholipase C, such as for a persistent elevation of [Ca ]i [1, 2, 12, 22, 24]. This polyunsaturated fatty acids or phosphatidylinositol 4,5- pathway for Ca2+ entry has often been referred to as store- 2+ 2+ bisphosphate (PIP2, 18,19). Molecular domains that are operated Ca channel (SOC) or ICRAC (intracellular Ca conserved in all members of the TRP family include release-activated Ca2+ influx
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