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Rooma desai

Xiaojuan Zhou, Rooma Desai, Yinghui Zhang, Wojciech J Stec, Keith W Miller, Youssef Jounaidi
The inhibitory γ-aminobutyric acid type A receptors are implicated in numerous physiological processes, including cognition and inhibition of neurotransmission, rendering them important molecular targets for many classes of drugs. Functionally, the entire GABAAR family of receptors can be subdivided into phasic, fast acting synaptic receptors, composed of α-, β- and γ-subunits, and tonic extrasynaptic receptors, many of which contain the δ-subunit in addition to α- and β-subunits. Whereas the subunit arrangement of the former group is agreed upon, that of the αβδ GABAARs remains unresolved by electrophysiological and pharmacological research...
2018: PloS One
Pavel Y Savechenkov, David C Chiara, Rooma Desai, Alexander T Stern, Xiaojuan Zhou, Alexis M Ziemba, Andrea L Szabo, Yinghui Zhang, Jonathan B Cohen, Stuart A Forman, Keith W Miller, Karol S Bruzik
Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAA R), but the locations of their GABAA R binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAA R, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAA R responses, left-shifting the GABA concentration - response curve for human α1β3γ2 GABAA Rs expressed in Xenopus oocytes, and enhancing [3 H]muscimol binding to α1β3γ2 GABAA Rs expressed in HEK293 cells...
August 18, 2017: European Journal of Medicinal Chemistry
Yalan Zhang, Xiao-Feng Zhang, Matthew R Fleming, Anahita Amiri, Lynda El-Hassar, Alexei A Surguchev, Callen Hyland, David P Jenkins, Rooma Desai, Maile R Brown, Valeswara-Rao Gazula, Michael F Waters, Charles H Large, Tamas L Horvath, Dhasakumar Navaratnam, Flora M Vaccarino, Paul Forscher, Leonard K Kaczmarek
Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane...
April 7, 2016: Cell
Rooma Desai, Pavel Y Savechenkov, Dorota Zolkowska, Ri Le Ge, Michael A Rogawski, Karol S Bruzik, Stuart A Forman, Douglas E Raines, Keith W Miller
KEY POINTS: Most barbiturates are anaesthetics but unexpectedly a few are convulsants whose mechanism of action is poorly understood. We synthesized and characterized a novel pair of chiral barbiturates that are capable of photolabelling their binding sites on GABAA receptors. In mice the S-enantiomer is a convulsant, but the R-enantiomer is an anticonvulsant. The convulsant S-enantiomer binds solely at an inhibitory site. It is both an open state inhibitor and a resting state inhibitor...
November 15, 2015: Journal of Physiology
Selwyn S Jayakar, Xiaojuan Zhou, Pavel Y Savechenkov, David C Chiara, Rooma Desai, Karol S Bruzik, Keith W Miller, Jonathan B Cohen
In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J...
September 18, 2015: Journal of Biological Chemistry
Zuzana Dostalova, Xiaojuan Zhou, Aiping Liu, Xi Zhang, Yinghui Zhang, Rooma Desai, Stuart A Forman, Keith W Miller
Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the most important inhibitory chloride ion channels in the central nervous system and are major targets for a wide variety of drugs. The subunit compositions of GABA(A)Rs determine their function and pharmacological profile. GABAA Rs are heteropentamers of subunits, and (α1)2 (β3)2 (γ2L)1 is a common subtype. Biochemical and biophysical studies of GABA(A)Rs require larger quantities of receptors of defined subunit composition than are currently available...
February 2014: Protein Science: a Publication of the Protein Society
Deirdre S Stewart, Mayo Hotta, Guo-Dong Li, Rooma Desai, David C Chiara, Richard W Olsen, Stuart A Forman
Etomidate is a potent general anesthetic that acts as an allosteric co-agonist at GABAA receptors. Photoreactive etomidate derivatives labeled αMet-236 in transmembrane domain M1, which structural models locate in the β+/α- subunit interface. Other nearby residues may also contribute to etomidate binding and/or transduction through rearrangement of the site. In human α1β2γ2L GABAA receptors, we applied the substituted cysteine accessibility method to α1-M1 domain residues extending from α1Gln-229 to α1Gln-242...
October 18, 2013: Journal of Biological Chemistry
Deirdre S Stewart, Mayo Hotta, Rooma Desai, Stuart A Forman
A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors. However, measuring agonist affinity in inactive receptors is confounded by concomitant activation. We identified a cysteine substituted mutant γ-aminobutyric acid type A (GABAA) receptor with unique characteristics allowing the determination of allosteric agonist site occupancy in both inactive and active receptors. Etomidate, the allosteric agonist, is an anesthetic that activates or modulates α1β2γ2L GABAA receptors via transmembrane sites near β2M286 residues in M3 domains...
June 2013: Molecular Pharmacology
Rooma Desai, Keith W Miller, Douglas E Raines
BACKGROUND: 5-Hydroxytryptamine type 3 (5-HT(3)) receptors are excitatory ion channels belonging to the cys-loop family of ligand-gated ion channels. They are involved in nausea and vomiting and their antagonists are used clinically as antiemetic drugs. We previously reported the development of a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties, but lacks its potent inhibitory effect on adrenocorticotropic hormone-stimulated steroid synthesis...
March 2013: Anesthesia and Analgesia
S Shaukat Husain, Deirdre Stewart, Rooma Desai, Ayman K Hamouda, S Guo-Dong Li, Elizabeth Kelly, Zuzana Dostalova, Xiaojuan Zhou, Joseph F Cotten, Douglas E Raines, Richard W Olsen, Jonathan B Cohen, Stuart A Forman, Keith W Miller
We synthesized the R- and S-enantiomers of ethyl 1-(1-(4-(3-((trifluoromethyl)-3H-diazirin-3-yl)phenyl)ethyl)-1H-imidazole-5-carboxylate (trifluoromethyldiazirinyl-etomidate), or TFD-etomidate, a novel photoactivable derivative of the stereoselective general anesthetic etomidate (R-(2-ethyl 1-(phenylethyl)-1H-imidazole-5-carboxylate)). Anesthetic potency was similar to etomidate's, but stereoselectivity was reversed and attenuated. Relative to etomidate, TFD-etomidate was a more potent inhibitor of the excitatory receptors, nAChR (nicotinic acetylcholine receptor) ((alpha1)(2)beta1delta1gamma1) and 5-HT(3A)R (serotonin type 3A receptor), causing significant inhibition at anesthetic concentrations...
September 9, 2010: Journal of Medicinal Chemistry
Zuzana Dostalova, Aiping Liu, Xiaojuan Zhou, Sarah L Farmer, Eileen S Krenzel, Enrique Arevalo, Rooma Desai, Paula L Feinberg-Zadek, Paul A Davies, Innocent H Yamodo, Stuart A Forman, Keith W Miller
The human neuronal Cys-loop ligand-gated ion channel superfamily of ion channels are important determinants of human behavior and the target of many drugs. It is essential for their structural characterization to achieve high-level expression in a functional state. The aim of this work was to establish stable mammalian cell lines that enable high-level heterologous production of pure receptors in a state that supports agonist-induced allosteric conformational changes. In a tetracycline-inducible stable human embryonic kidney cells (HEK293S) cell line, GABA(A) receptors containing α1 and β3 subunits could be expressed with specific activities of 29-34 pmol/mg corresponding to 140-170 pmol/plate, the highest expression level reported so far...
September 2010: Protein Science: a Publication of the Protein Society
Rooma Desai, Dirk Ruesch, Stuart A Forman
BACKGROUND: Etomidate acts at gamma-Aminobutyric acid type A (GABAA) receptors containing beta2 or beta3, but not beta1 subunits. Mutations at beta residue 265 (Ser in beta1; Asn in beta2 or beta3) profoundly affect etomidate sensitivity. Whether these mutations alter etomidate binding remains uncertain. METHODS: Heterologously expressed alpha1beta2gamma2L GABAA receptors and receptors with beta2(N265S) or beta2(N265M) mutations were studied electrophysiologically in both Xenopus oocytes and HEK293 cells...
October 2009: Anesthesiology
Deirdre Stewart, Rooma Desai, Qi Cheng, Aiping Liu, Stuart A Forman
The potent general anesthetic etomidate produces its effects by enhancing GABA(A) receptor activation. Its photolabel analog [(3)H]azi-etomidate labels residues within transmembrane domains on alpha and beta subunits: alphaMet236 and betaMet286. We hypothesized that these methionines contribute to etomidate sites formed at alpha-beta subunit interfaces and that increasing side-chain bulk and hydrophobicity at either locus would mimic etomidate binding and block etomidate effects. Channel activity was electrophysiologically quantified in alpha(1)beta(2)gamma(2L) receptors with alpha(1)M236W or beta(2)M286W mutations, in both the absence and the presence of etomidate...
December 2008: Molecular Pharmacology
Rooma Desai, Jack Kronengold, Jianfeng Mei, Stuart A Forman, Leonard K Kaczmarek
Modulation of some Kv3 family potassium channels by protein kinase C (PKC) regulates their amplitude and kinetics and adjusts firing patterns of auditory neurons in response to stimulation. Nevertheless, little is known about the modulation of Kv3.3, a channel that is widely expressed throughout the nervous system and is the dominant Kv3 family member in auditory brainstem. We have cloned the cDNA for the Kv3.3 channel from mouse brain and have expressed it in a mammalian cell line and in Xenopus oocytes to characterize its biophysical properties and modulation by PKC...
August 8, 2008: Journal of Biological Chemistry
Bo Yang, Rooma Desai, Leonard K Kaczmarek
The Slack (sequence like a calcium-activated K channel) and Slick (sequence like an intermediate conductance K channel) genes, which encode sodium-activated K+ (K(Na)) channels, are expressed at high levels in neurons of the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem. These neurons lock their action potentials to incoming stimuli with a high degree of temporal precision. Channels with unitary properties similar to those of Slack and/or Slick channels, which are gated by [Na+]i and [Cl-]i and by changes in cytoplasmic ATP levels, are present in MNTB neurons...
March 7, 2007: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Richard A Flavell, Leonard K Kaczmarek, Abdallah Badou, Emile L Boulpaep, Rooma Desai, Srisaila Basavappa, Didi Matza, You-Qing Peng, Wajahat Z Mehal
No abstract text is available yet for this article.
December 23, 2005: Science
Leonard K Kaczmarek, Arin Bhattacharjee, Rooma Desai, Li Gan, Ping Song, Christian A A von Hehn, Matthew D Whim, Bo Yang
The firing patterns of neurons in central auditory pathways encode specific features of sound stimuli, such as frequency, intensity and localization in space. The generation of the appropriate pattern depends, to a major extent, on the properties of the voltage-dependent potassium channels in these neurons. The mammalian auditory pathways that compute the direction of a sound source are located in the brainstem and include the connection from bushy cells in the anteroventral cochlear nucleus (AVCN) to the principal neurons of the medial nucleus of the trapezoid body (MNTB)...
August 2005: Hearing Research
Abdallah Badou, Srisaila Basavappa, Rooma Desai, You-Qing Peng, Didi Matza, Wajahat Z Mehal, Leonard K Kaczmarek, Emile L Boulpaep, Richard A Flavell
Calcium is known to play vital roles in diverse physiological processes, and it is known that voltage-gated calcium channels (Cav) mediate calcium influx in excitable cells. However, no consensus exists on the molecular identity of the calcium channels present in nonexcitable cells such as T lymphocytes. Here, we demonstrate that T lymphocytes express both regulatory beta4 and poreforming Cav1 alpha1 subunits of Cav channels. Cav beta4-mutant T lymphocytes fail to acquire normal functions and display impairment in the calcium response, activation of the transcription factor NFAT, and cytokine production...
January 7, 2005: Science
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