Riccardo Olcese, Ph.D.

Office Address:
100 Jules Stein Plaza
Division of Molecular Medicine
Dept. of Anesthesiology and Perioperative Medicine
Los Angeles, CA 90095

Work Address:
CHS
Los Angeles, CA 90095

Affiliations
Affiliations
Professor, Anesthesiology, Physiology
Member, Molecular Medicine, Biochemistry, Biophysics & Structural Biology GPB Home Area, Brain Research Institute, Molecular, Cellular & Integrative Physiology GPB Home Area, Neuroscience GPB Home Area
Faculty, Cardiovascular Research Laboratory
Research Interests
The general aim of my research is to define the role of ion channels in the control and regulation of cell excitability. Ion channels are membrane proteins that regulate the flow of ions across the cell membrane that in turn control a variety of functions such as neuronal excitability, heartbeat, muscle contraction and hormones release. Ion channels are transmembrane proteins usually associated with accessory subunits that modulate their function. The regulation mechanism(s) of voltage dependent channel activity by accessory subunits and second messengers is one of my strongest interests. In these studies, by combining state-of-the-art electrophysiological techniques (cut-open oocyte voltage clamp, patch clamp, macropatch) with mutagenesis, we identifying the structural determinants for the various channel functions (activation, inactivation, conduction and sensitivity to drugs). STRUCTUTRAL REARRANGEMENTS OF CHANNEL PROTEINS DURING GATING Voltage-dependent ion channels respond to changes of membrane potential by a rearrangement of a voltage sensing structure. The movement of the voltage sensor produces a conformational change of the channel that allows ion conduction through the pore. Part of my research is currently dedicated to understand the coupling mechanism between the movements of the voltage sensor and pore opening. This study involves the measurement of small currents (gating currents) generated by the movement of the charged voltage sensor across the transmembrane electric field. Gating currents reveal the conformational changes of the channel protein, occurring before and during channel opening. In this research program, we combine optical methods with classical electrophysiology to detect conformational changes of the channels. This novel approach in ion channels studies allows detecting conformational changes of channel protein as changes in fluorescence properties of fluorophores covalently attached to selected positions on the protein (voltage clamp + site directed fluorescence labeling). One of the goals is to correlate at the molecular level the structural changes of the channel protein with the different phases of channel activity. At this moment, I am using this approach to investigate the properties of voltage and calcium activated (BK) channels. The final objective is to obtain a molecular and dynamic view of BK channels by identifying the mobile regions underlying voltage sensing. MECHANISMS OF ION PERMEATION THROUGH ION CHANNEL: We are currently investigating how the amino acids in close proximity of the conduction pore are affecting the conduction properties of voltage- and calcium-activated K+ channels. In combination with theoretical, biophysical and pharmacological studies, we learn about the basic mechanism of ion permeation and channel gating at the molecular level. One of the objectives is to understand the unique permeation properties of BK channels, which allow K+ to permeate 20fold better in respect to other potassium channels that share very similar amino acid pore sequences. CARDIAC ARRHYTHMIAS AND FIBRILLATION In collaboration with Dr J. Weiss, we are developing a research program focused cardiac arrhythmias and fibrillation. Activation and inactivation of voltage dependent calcium channels play a key role in the stability of the cardiac rhythm, through their effects on action potential properties. The goal is to is to control cardiac excitability, by fine tuning the the activity of cardiac L-type calcium channels using their own modulatory subunits. The project should set basis for a larger gene-therapy related project
Publications

A selected list of publications:

Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R.   The RCK2 domain of the human BKCa channel is a calcium sensor, Proc Natl Acad Sci U S A, 2008; 105(1): 376-81.
Mahajan A, Shiferaw Y, Sato D, Baher A, Olcese R, Xie LH, Yang MJ, Chen PS, Restrepo JG, Karma A, Garfinkel A, Qu Z, Weiss JN. 2008   A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates, Biophys J, 2008; 94(2): 392-410.
Mahajan A, Sato D, Shiferaw Y, Baher A, Xie LH, Peralta R, Olcese R, Garfinkel A, Qu Z, Weiss JN.   Modifying L-type calcium current kinetics: consequences for cardiac excitation and arrhythmia dynamics, Biophys J. , 2008; 94(2): 411-23. .
Olcese Riccardo   And yet it moves: conformational States of the Ca2+ channel pore, J Gen Physiol. , 2007; 129(6)((6)): 457-9..
Gudzenko V, Shiferaw Y, Savalli N, Vyas R, Weiss JN, Olcese R.   Influence of channel subunit composition on L-type Ca2+ current kinetics and cardiac wave stability, Am J Physiol Heart Circ Physiol, 2007; 293(3): H1805-15.
Savalli N, Kondratiev A, de Quintana SB, Toro L, Olcese R.   Modes of operation of the BKCa channel beta2 subunit, J Gen Physiol, 2007; 130((1)): 117-31.
Savalli N, Kondratiev A, Toro L, Olcese R.   Voltage-dependent conformational changes in human Ca(2+)- and voltage-activated K(+) channel, revealed by voltage-clamp fluorometry, Proc Natl Acad Sci U S A. , 2006; 103(33): 12619-24.
Chen ZW, Chang CS, Leil TA, Olcese R, Olsen RW.   GABAA receptor-associated protein regulates GABAA receptor cell-surface number in Xenopus laevis oocytes, Mol Pharmacol, 2005; 68(1): 152-9..
Haug T., Olcese, R., Ciani S, Toro L., Stefani, E.   Regulation of inward K flow by a negative residue in the outer vestibule of the MaxiK channel pore Part I, Journal of General Physiology, 2004; 124(2): 185-97.
Haug T, Ciani S, Toro L., Stefani, Olcese, R.   Regulation of inward K flow by a negative residue in the outer vestibule of the MaxiK channel pore Part II, Journal of General Physiology, 2004; 124(2): 173-184.
Chang CS., Olcese, R., and R. Olsen   A single M1 residue in the beta2 subunit alters channel gating of GAGAA receptor in anesthetic modulation and direct activation, Journal of Biological Chemistry, 2003; 278(44): 42821.
Latorre R.,Olcese R.,Basso C.,Gonzalez C., Munoz F.,Cosmelli D. and Osvaldo Alvarez.   Molecular coupling between voltage sensor and pore opening in the Arabidopis inward rectifier K+ channel KAT1, Journal of General Physiology, 2003; 122(4): 459-469.
Helguera G., Olcese, R., Song M., Toro L. and Stefani E.   Tissue-specific regulation of K+ and Ca2+ channel protein expression, Biochimica et Biophysica Acta, 2002; 1569(1-3): 59-66.
Eghbali, M Olcese, R Zarei, MM Toro, L Stefani, E   External pore collapse as an inactivation mechanism for Kv4.3 K+ channels The Journal of membrane biology. , 2002; 188(1): 73-86.
Olcese, R., Sigg D., Bezanilla F., Stefani E   A conducting state with properties of a slow inactivated state in Shaker K+ channel mutant, Journal of General Physiology , 2001; 117: 149-163.
Platano, D. Qin N., Birnbaumer L., Stefani, E. and Olcese, R.   Alpha-2-delta subunit interferes with prepulse facilitation in L-type Ca2+ channels, Biophysical Journal, 2000; 78: 2959-2972.
Noceti, F., Olcese, R., Qin, N., Birnbaumer, L., and Stefani, E.   Effect of Bay K 8644(-) and the b2a subunit on Ca2+ dependent inactivation in a1C Ca2+ channels: A model, , 1998; 111(3): 463-475.
Roux, M., Olcese, R., Toro, L., Bezanilla, F. and Stefani, E.   Fast inactivation in Shaker K+ channels: properties of ionic and gating currents, , 1998; 111: 625-638.
Qin N, Olcese, R., Stefani, E., and Birnbaumer L.   Modulation of human neuronal a1E calcium channel by a2d ?subunit, , 1998; 274: C1324-1331.
Birnbaumer. L., Qin N., Olcese, R., Tareilus E., Platano, D., Costantin J. and Stefani, E.   Structures and functions of calcium channel b subunits, J. of Bioenergy and Biomembrane, 1998; 30(4): 357-375.
Qin, N., Platano, D., Olcese, R., Constantin J.L., Stefani, E., and Birnbaumer, L.   Unique regulatory properties of type 2a Ca2+ channel b ?subunit due to palmitoylation, , 1998; 95: 4690-4695.
Stefani, E., Ottolia, M., Noceti, F., Olcese, R., Wallner, M., and Latorre, R.   Calcium independent and voltage-controlled gating in a Ca2+-sensitive K+ channel (hslo). Proceedings of National Academy of Science USA, , 1997; 94: 5427-5431.
Olcese, R., Neely, A.,Qin, N., Wei, X., Birnbaumer, L., and Stefani, E.   Coupling between charge movement and pore opening in type-E Ca2+ channel, Journal of Physiology, 1997; 497: 675-686.
Qin, N., Platano, D., Olcese, R., Stefani, E., and Birnbaumer, L.   Direct interaction of Gbg with a novel C-terminal Gbg binding domain of a1 is responsible for inhibition of presynaptic Ca2+ channels by G-protein-coupled receptors, Proceedings of National Academy of Science USA, 1997; 94: 8866-8871.
Nobile, M., Olcese, R., Toro, L., and Stefani, E.   Fast inactivation of Shaker K+ channels is highly temperature dependent, Experimental Brain Research, 1997; 114 (1):: 138-142.
Zhou, J., Olcese, R., Qin, N., Birnbaumer, L. and Stefani, E.   Feedback inhibition of calcium channels by calcium depends on a short sequence of carboxy terminus that does not include the calcium binding function of a motif with similarity to calcium binding domains, , 1997; 94: 2301-2305.
Olcese, R., Noceti, F., Baldelli, P., Qin, N., Birnbaumer, L. and Stefani, E.   beta subunit modulation of the coupling between charge movement and pore opening in calcium channels, From ion channels to cell to cell conversation, 1997; 91-104.
Tareilus, E. Roux, M., Qin, N., Olcese, R., Zhou, J., Stefani, E. and Birnbaumer, L.   A Xenopus Oocytes b subunit: evidence for a role in Assembly/expression of voltage-gated calcium channels that is separated from a role as a regulatory subunit, Proceedings of National Academy of Science USA, 1996; 94: 1703-170.
Qin, N., Olcese, R., Zhou, J., Cabello, O.A., Birnbaumer, L. and Stefani E.   Identification of a second region of the b subunit involved in the regulation of calcium channel inactivation, American Journal of Physiology, 1996; 271: C1539-C1545.
Wei, X., Neely, A., Olcese, R., Stefani, E., and Birnbaumer, L.   Increase in Ca2+ channel expression by deletions at the amino terminus of the cardiac a1 subunit. Receptors and channels, , 1996; 4 (4):: 205-215.
Neely, A., Olcese, R., Wei, X., Baldelli, P., Birnbaumer, L. and Stefani E.   Dual activation kinetic in cloned calcium channel and its modulation by the b subunit, American Journal of Physiology, 1995; 268: C732-C740.
Neely, A., Olcese, R., Wei, X., Birnbaumer, L. and Stefani E.   Calcium-dependent inactivation of cardiac calcium channels expressed in Xenopus oocytes, Biophysical J, 1994; 66 (6): 1895-1903.
Wei, X., Neely, A., Lacerda, A.E., Olcese, R., Stefani, E., and Birnbaumer, L.   Modification of Ca2+ channel activity by deletions at the carboxyl terminus of the cardiac a1 subunit, J. Biol. Chem, 1994; 239 (3):: 1635-40.
Schneider, T., Wei, X., Olcese, R., Costantin J.L., Neely, A., Palade, P., Perez-Reyes, E.; Pan, S., Qin, N., Zhou, J., Crawford, G.D., Smith, R.G., Appel, S.H., Stefani, E., and Birnbaumer, L.   Molecular analysis and functional expression of the human type E neuronal Ca2+ channel a1 subunit, Receptors and Channels, 1994; 2: 255-270.
Neely, A., Wei, X., Olcese, R., Birnbaumer, L., and Stefani E.   Potentiation by the b subunit of the ratio of the ionic current to charge movement in the cardiac calcium channel, Science, 1993; 262: 575-578.
Qin, N Olcese, R Bransby, M Lin, T Birnbaumer, L   Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin Proceedings of the National Academy of Sciences of the United States of America. , 1999; 96(5): 2435-8.
Olcese, R Latorre, R Toro, L Bezanilla, F Stefani, E   Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels The Journal of general physiology. , 1997; 110(5): 579-89.
Olcese, R Qin, N Schneider, T Neely, A Wei, X Stefani, E Birnbaumer, L   The amino terminus of a calcium channel beta subunit sets rates of channel inactivation independently of the subunit's effect on activation Neuron. , 1994; 13(6): 1433-8.
Olcese, R Usai, C Maestrone, E Nobile, M   The general anesthetic propofol inhibits transmembrane calcium current in chick sensory neurons Anesthesia and analgesia. , 1994; 78(5): 955-60.
Prudat Yann, Madhvani Roshni V, Angelini Marina, Borgstom Nils P, Garfinkel Alan, Karagueuzian Hrayr S, Weiss James N, de Lange Enno, Olcese Riccardo, Kucera Jan P   Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics The Journal of physiology, 2015; .
Madhvani Roshni V, Angelini Marina, Xie Yuanfang, Pantazis Antonios, Suriany Silvie, Borgstrom Nils P, Garfinkel Alan, Qu Zhilin, Weiss James N, Olcese Riccardo   Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations The Journal of general physiology, 2015; 145(5): 395-404.
Weiss James N, Garfinkel Alan, Karagueuzian Hrayr S, Nguyen Thao P, Olcese Riccardo, Chen Peng-Sheng, Qu Zhilin   Perspective: a dynamics-based classification of ventricular arrhythmias Journal of molecular and cellular cardiology, 2015; 82(5): 136-52.
Pantazis Antonios, Savalli Nicoletta, Sigg Daniel, Neely Alan, Olcese Riccardo   Functional heterogeneity of the four voltage sensors of a human L-type calcium channel Proceedings of the National Academy of Sciences of the United States of America, 2014; 111(51): 18381-6.
Qu Zhilin, Xie Lai-Hua, Olcese Riccardo, Karagueuzian Hrayr S, Chen Peng-Sheng, Garfinkel Alan, Weiss James N   Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve Cardiovascular research, 2013; 99(1): 6-15.
Pantazis Antonios, Olcese Riccardo   Relative transmembrane segment rearrangements during BK channel activation resolved by structurally assigned fluorophore-quencher pairing The Journal of general physiology, 2012; 140(2): 207-18.
Savalli Nicoletta, Pantazis Antonios, Yusifov Taleh, Sigg Daniel, Olcese Riccardo   The contribution of RCK domains to human BK channel allosteric activation The Journal of biological chemistry, 2012; 287(26): 21741-50.
Madhvani Roshni V, Xie Yuanfang, Pantazis Antonios, Garfinkel Alan, Qu Zhilin, Weiss James N, Olcese Riccardo   Shaping a new Ca²⁺ conductance to suppress early afterdepolarizations in cardiac myocytes The Journal of physiology, 2011; 589(Pt 24): 6081-92.
Javaherian Anoosh D, Yusifov Taleh, Pantazis Antonios, Franklin Sarah, Gandhi Chris S, Olcese Riccardo   Metal-driven operation of the human large-conductance voltage- and Ca2+-dependent potassium channel (BK) gating ring apparatus The Journal of biological chemistry, 2011; 286(23): 20701-9.
Olcese Riccardo   I(KACh) at the whim of a capricious M2R The Journal of physiology, 2011; 589(Pt 8): 1869-70.
Pantazis Antonios, Kohanteb Azadeh P, Olcese Riccardo   Relative motion of transmembrane segments S0 and S4 during voltage sensor activation in the human BK(Ca) channel The Journal of general physiology, 2010; 136(6): 645-57.
Yusifov Taleh, Javaherian Anoosh D, Pantazis Antonios, Gandhi Chris S, Olcese Riccardo   The RCK1 domain of the human BKCa channel transduces Ca2+ binding into structural rearrangements The Journal of general physiology, 2010; 136(2): 189-202.
Pantazis Antonios, Gudzenko Vadym, Savalli Nicoletta, Sigg Daniel, Olcese Riccardo   Operation of the voltage sensor of a human voltage- and Ca2+-activated K+ channel Proceedings of the National Academy of Sciences of the United States of America, 2010; 107(9): 4459-64.
Olcese Riccardo   It's spring-time for slow inactivation The Journal of general physiology, 2009; 134(6): 457-9.
Gandhi Chris S, Olcese Riccardo   The voltage-clamp fluorometry technique Methods in molecular biology (Clifton, N.J.), 2008; 491(6): 213-31.
Helguera Gustavo, Olcese Riccardo, Song Min, Toro Ligia, Stefani Enrico   Tissue-specific regulation of Ca(2+) channel protein expression by sex hormones Biochimica et biophysica acta, 2002; 1569(1-3): 59-66.
Haug Trude, Olcese Riccardo, Toro Ligia, Stefani Enrico   Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part II: Neutralization of aspartate 292 reduces long channel openings and gating current slow component The Journal of general physiology, 2004; 124(2): 185-97.
Haug Trude, Sigg Daniel, Ciani Sergio, Toro Ligia, Stefani Enrico, Olcese Riccardo   Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part I: Aspartate 292 modulates K+ conduction by external surface charge effect The Journal of general physiology, 2004; 124(2): 173-84.
Zhang Jin, Li Min, Zhang Zhu, Zhu Ronghui, Olcese Riccardo, Stefani Enrico, Toro Ligia   The mitochondrial BKCa channel cardiac interactome reveals BKCa association with the mitochondrial import receptor subunit Tom22, and the adenine nucleotide translocator Mitochondrion, 2017; 33: 84-101.
Chang Chang-sheng S, Olcese Riccardo, Olsen Richard W   A single M1 residue in the beta2 subunit alters channel gating of GABAA receptor in anesthetic modulation and direct activation The Journal of biological chemistry, 2003; 278(44): 42821-8.
Karagueuzian Hrayr S, Pezhouman Arash, Angelini Marina, Olcese Riccardo   Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets Frontiers in pharmacology, 2017; 8: 36.
Latorre Ramon, Olcese Riccardo, Basso Claudia, Gonzalez Carlos, Munoz Fabian, Cosmelli Diego, Alvarez Osvaldo   Molecular coupling between voltage sensor and pore opening in the Arabidopsis inward rectifier K+ channel KAT1 The Journal of general physiology, 2003; 122(4): 459-69.
Savalli Nicoletta, Pantazis Antonios, Sigg Daniel, Weiss James N, Neely Alan, Olcese Riccardo   The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials The Journal of general physiology, 2016; 148(2): 147-59.