Central Nervous System; Electrophysiology; Kidney; Nephrology; Physiology; Epithelial Sodium Channels
Cellular & Molecular Physiology: Epithelial Transport of Ions and Solutes | Membrane Biophysics | Membrane Proteins - Ion Channels | Physiology of Human Disease
The main interest in our laboratory is to elucidate the structure-function and regulation of ion channels from the ENaC/Degenerin family specifically by a set of S/T kinases known as glococorticoid-induced kinases (Sgk). Some of these channels such as ENaC are expressed in kidney where they retain sodium and thereby are key contributors for the maintenance and regulation of blood pressure.
The mammalian Degenerins or ASICs are channels expressed in the peripheral and central nervous system where they may regulate membrane excitability and thus contribute to many neuronal processes. We employ a broad variety of approaches that include molecular and cell biological techniques and electrophysiological measurements of channel activity by patch clamp techniques on cultured cells and tissues. We also develop mouse models expressing mutant channels or Sgk kinases to examine the physiological and pathophysiological consequences of altered channel function in blood pressure and in the nervous system.
Specialized Terms: Renal Function; Epithelial Sodium Channels
Extensive Research Description
our laboratory we examine the structure, function and regulation of two
types of sodium channels: the Epithelial Na + Channel (ENaC) and Acid
Sensing Ion Channels (ASIC). These proteins are structurally related
but serve very different functions. ENaC is expressed in the apical
side of epithelial cells involved in sodium absorption such as in
kidney, lung and colon. Mutations in the human ENaC genes produce
disorders of whole-body sodium balance and are characterized by
hypertension or sodium wasting. Our current work centers on mechanisms
that regulate activity, expression and traffic of ENaC in epithelial
cells specifically, on the role of a kinase known as serum-and
glucocorticoid-induced kinase or Sgk1.
The ASICs are expressed in neurons of the central and peripheral nervous systems. External protons gate ASIC but other stimuli are likely to be more important physiological agonists. These channels have been implicated in many functions including nociception, mechanoperception and modulation of synaptic transmission. Our work centers in the elucidation of the biophysical properties and gating of ASICs from many vertebrate species.
We use a broad range of experimental approaches and techniques that include electrophysiology (patch-clamp, two-electrode voltage clamp, short-circuit current), cloning of channels from evolutionary distant species, modifications of channels and their expression in oocytes, cell lines and in mice either trangenics or knockins.
Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1
Arteaga MF, Alvarez de la Rosa D, Alvarez JA, Canessa CM. Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1. Mol Biol Cell, 18:2072-80, 2007.
A short amphipathic helix targets Sgk1 to the ER-associated ubiquitin-conjugation machinery
Arteaga MF, Wang L, Ravid T, Hochstrasser M, Canessa CM. A short amphipathic helix targets Sgk1 to the ER-associated ubiquitin-conjugation machinery. Proc Natl Acad Sci USA, 103:11178-83, 2006.
Gating of acid-sensitive ion channel-1: Release of Ca<sup>2+</sup> block vs. allosteric mechanism
Zhang P, Sigworth FJ, Canessa CM. Gating of acid-sensitive ion channel-1: Release of Ca<sup>2+</sup> block vs. allosteric mechanism. J Gen Physiol, 127:109-17, 2006.
SGK1 activates Na<sup>+</sup>-K<sup>+</sup>-ATPase in amphibian renal epithelial cells
Alvarez de la Rosa D, Gimenez I, Forbush B, Canessa CM. SGK1 activates Na<sup>+</sup>-K<sup>+</sup>-ATPase in amphibian renal epithelial cells. Am J Physiol Cell Physiol, 290:C492-8, 2006.
Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel
Coric T, Zheng D, Gerstein M, Canessa CM. Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel. J Physiol, 568:725-35, 2005.
Full List of PubMed Publications
- González-Fernández R, Ávila J, Arteaga MF, Canessa CM, Martín-Vasallo P: The neuronal-specific SGK1.1 (SGK1_v2) kinase as a transcriptional modulator of BAG4, Brox, and PPP1CB genes expression. Int J Mol Sci. 2015 Apr 2; 2015 Apr 2. PMID: 25849655
- Li T, Yang Y, Canessa CM: A method for activation of endogenous acid-sensing ion channel 1a (ASIC1a) in the nervous system with high spatial and temporal precision. J Biol Chem. 2014 May 30; 2014 Apr 11. PMID: 24727474
- Li T, Yang Y, Canessa CM: Impact of recovery from desensitization on acid-sensing ion channel-1a (ASIC1a) current and response to high frequency stimulation. J Biol Chem. 2012 Nov 23; 2012 Oct 9. PMID: 23048040
- Li T, Yang Y, Canessa CM: Outlines of the pore in open and closed conformations describe the gating mechanism of ASIC1. Nat Commun. 2011 Jul 19; 2011 Jul 19. PMID: 21772270
- Li T, Yang Y, Canessa CM: Asp433 in the closing gate of ASIC1 determines stability of the open state without changing properties of the selectivity filter or Ca2+ block. J Gen Physiol. 2011 Mar. PMID: 21357733
- Li T, Yang Y, Canessa CM: Asn415 in the beta11-beta12 linker decreases proton-dependent desensitization of ASIC1. J Biol Chem. 2010 Oct 8; 2010 Jul 30. PMID: 20675379
- Li T, Yang Y, Canessa CM: Leu85 in the beta1-beta2 linker of ASIC1 slows activation and decreases the apparent proton affinity by stabilizing a closed conformation. J Biol Chem. 2010 Jul 16; 2010 May 17. PMID: 20479002
- Li T, Yang Y, Canessa CM: Two residues in the extracellular domain convert a nonfunctional ASIC1 into a proton-activated channel. Am J Physiol Cell Physiol. 2010 Jul; 2010 Apr 28. PMID: 20427715
- Li T, Yang Y, Canessa CM: Interaction of the aromatics Tyr-72/Trp-288 in the interface of the extracellular and transmembrane domains is essential for proton gating of acid-sensing ion channels. J Biol Chem. 2009 Feb 13; 2008 Dec 11. PMID: 19074149
- Coric T, Passamaneck YJ, Zhang P, Di Gregorio A, Canessa CM: Simple chordates exhibit a proton-independent function of acid-sensing ion channels. FASEB J. 2008 Jun; 2008 Jan 22. PMID: 18211956
- Arteaga MF, Coric T, Straub C, Canessa CM: A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons. Proc Natl Acad Sci U S A. 2008 Mar 18; 2008 Mar 11. PMID: 18334630
- Arteaga MF, Alvarez de la Rosa D, Alvarez JA, Canessa CM: Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1. Mol Biol Cell. 2007 Jun; 2007 Mar 21. PMID: 17377066
- Arteaga MF, Wang L, Ravid T, Hochstrasser M, Canessa CM: An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc Natl Acad Sci U S A. 2006 Jul 25; 2006 Jul 17. PMID: 16847254
- Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC: WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). J Physiol. 2006 Mar 1; 2005 Dec 15. PMID: 16357011
- Zhang P, Sigworth FJ, Canessa CM: Gating of acid-sensitive ion channel-1: release of Ca2+ block vs. allosteric mechanism. J Gen Physiol. 2006 Feb; 2006 Jan 17. PMID: 16418400
- Coric T, Zheng D, Gerstein M, Canessa CM: Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel. J Physiol. 2005 Nov 1; 2005 Jul 7. PMID: 16002453
- Arteaga MF, Canessa CM: Functional specificity of Sgk1 and Akt1 on ENaC activity. Am J Physiol Renal Physiol. 2005 Jul. PMID: 15951481
- Mobasheri A, Barrett-Jolley R, Shakibaei M, Canessa CM, Martín-Vasallo P, Kamkin A, Kiseleva I: Enigmatic Roles of the Epithelial Sodium Channel (ENaC) in Articular Chondrocytes and Osteoblasts: Mechanotransduction, Sodium Transport or Extracellular Sodium Sensing? 2005. PMID: 21290775
- Zhang YH, Alvarez de la Rosa D, Canessa CM, Hayslett JP: Insulin-induced phosphorylation of ENaC correlates with increased sodium channel function in A6 cells. Am J Physiol Cell Physiol. 2005 Jan; 2004 Sep 8. PMID: 15355850
- Alvarez de la Rosa D, Paunescu TG, Els WJ, Helman SI, Canessa CM: Mechanisms of regulation of epithelial sodium channel by SGK1 in A6 cells. J Gen Physiol. 2004 Oct. PMID: 15452200
- Coric T, Hernandez N, Alvarez de la Rosa D, Shao D, Wang T, Canessa CM: Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2004 Apr; 2003 Nov 20. PMID: 14630642
- Coric T, Zhang P, Todorovic N, Canessa CM: The extracellular domain determines the kinetics of desensitization in acid-sensitive ion channel 1. J Biol Chem. 2003 Nov 14; 2003 Aug 28. PMID: 12947112
- Alvarez de la Rosa D, Canessa CM: Role of SGK in hormonal regulation of epithelial sodium channel in A6 cells. Am J Physiol Cell Physiol. 2003 Feb; 2002 Oct 16. PMID: 12388075
- Alvarez de la Rosa D, Krueger SR, Kolar A, Shao D, Fitzsimonds RM, Canessa CM: Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J Physiol. 2003 Jan 1. PMID: 12509480
- Zhang P, Canessa CM: Single channel properties of rat acid-sensitive ion channel-1alpha, -2a, and -3 expressed in Xenopus oocytes. J Gen Physiol. 2002 Oct. PMID: 12356856
- Alvarez de la Rosa D, Li H, Canessa CM: Effects of aldosterone on biosynthesis, traffic, and functional expression of epithelial sodium channels in A6 cells. J Gen Physiol. 2002 May. PMID: 11981022
- Alvarez de la Rosa D, Zhang P, Shao D, White F, Canessa CM: Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. Proc Natl Acad Sci U S A. 2002 Feb 19; 2002 Feb 12. PMID: 11842212