SRINIVAS N PENTYALA, Ph.D.

Associate Professor, Departments of Anesthesiology, Physiology & Biophysics, Urology

Director of Translational Research, Department of Anesthesiology

School of Medicine, State University of New York

Stony Brook, NY 11794-8480, USA.

Ph: 516-444-2974 Fax: 516-444-2907

PROJECT I :

My research interests are to understand the effect of volatile anesthetics on a set of potential molecular targets, the heterotrimeric GTP-binding proteins. Perturbation of ligand-gated ion channels as a molecular basis for anesthesia is a very appealing idea because it translates directly into changes in channel activity and thereby neuronal excitability. Nevertheless, these changes in electrical activity are not necessarily the direct result of anesthetic binding to channels or perturbation of the surrounding lipid. An alternative view is that volatile agents disrupt pathways controlled by metabotropic receptors, which are coupled to signal-generating enzymes and ion channels through heterotrimeric GTP-binding (G) proteins. Various metabotropic receptors, including muscarininc, adrenergic, serotinergic and GABAb receptors modulate consciousness, memory and nociception through G-protein coupled pathways, altering the responsiveness of ligand and voltage-gated ion channels. These receptors exert indirect control on channel activity by second messenger-regulated protein kinases and phosphatases, while more direct control involves a membrane-delimited association of the channel and active G-protein subunits. At sub-anesthetic doses, halothane, isoflurane, and sevoflurane inhibited exchange of GTP for GDP bound to G- subunits; enflurane was also effective, but only at doses less than the EC₅₀ dose in humans. Likewise, these agents markedly enhanced the rates of dissociation of GTP, but not GDP. By contrast, when G-alpha_o and the low molecular weight G-protein, ras, were examined, neither the rates of exchange nor dissociation were affected. Its concluded that many of the volatile agents, at clinically relevant doses, have a direct effect on the conformation and stability of the GTP/Mg²⁺ bound state of most, but not all G-alpha subunits. By destabilzing the GTP/Mg²⁺-charged state, volatile agents uncouple signaling pathways controlled by metabotropic receptors. Studies are being extended to evaluate the possible effects of these drugs on cell signaling involving calcium movements, alpha-2 receptor/G-protein complex, intrinsic GTPase activity, Phospholipases, G-protein/adenylate cyclase complex and adenylate cyclase itself.

PROJECT II :

Intravenous anesthetics are reported to be a bronchial smooth muscle dialator and has been proposed for use in asthmatic patients. Clinical studies have shown that I.V. anesthetics (ketamine and others) are not only useful in protecting against the precipitation of asthma in an asymptomatic patient, but that also relieves the symptoms of asthma at the time of induction of anesthesia. It was shown that the higher the initial airway resistance, the more pronounced the improvement in airway conductance in response to I.V. anesthetics. I.V. anesthetic mediated relaxation of airway smooth muscle has been associated with disruption of Ca²⁺ movements, however the exact mechanism is still unclear. To assess further the action of I.V. anesthetics, differential effects on pressure responses and Ca²⁺ flux in model systems like RBC, vascular smooth muscle cells and peripheral airways (guinea pig isolated liquid-airway perfused lung preparation) are being studied.

PROJECT III :

In association with the Department of Physiology and Biophysics, the interaction of Phospholipase C isozymes on membrane phospholipids is also being studied. As part of the project purification of alpha, beta-gamma and gamma subunits of G-protein, different individual domains of phospholipase C (PH, C2) were recombinantly expressed and their possible interaction with the membrane proteins is being studied. Domain swapping between different isozymes is underway to fully understand the physiological role of different PLC isozymes. To study the physiological aspect of PLC, whole and truncated enzyme is linked to Green fluorescent protein as fusion chimera and is being studied, using confocal technique. Also subunits of the heterotrimer G-protein were purified and interaction of PLC's with alpha and beta-gamma subunits, membranes and receptors is being studied. Using the GFP expression systems, studies are underway to elucidate the role of PLC-delta 1 in living cells using confocal microscopy. The studies are particularly targeted to understand the role of PLC-delta as a key player in apoptosis and signal amplifier.

SELECTED PUBLICATIONS

Chughtai B, Sawas A, O'Malley RL, Khan SA, Pentyala SN. A  Neglected  Gland:  A  Review  of  Cowper’s  Gland. Int J Androl. 2005 Apr;28(2):74-7

Stallings JD, Tall EG, Pentyala S, Rebecchi MJ. Nuclear translocation of phospholipase C-δ1 is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2005 Apr 4

Gambhir A, Hangyas-Mihalyne G, Zaitseva I, Cafiso DS, Wang J, Murray D, Pentyala SN, Smith SO, McLaughlin S. Electrostatic Sequestration of PIP(2) on Phospholipid Membranes by Basic/Aromatic Regions of Proteins. Biophys J. 2004 Apr;86(4):2188-207

Kondabolu S, Khan SA, Diblasio C, Pentyala SN The role of endoluminal ultrasonography in urology: Current perspectives. Braz J Urol 30: 96-101, 2004

Murthy KS, Zhou H, Huang J, Pentyala SN Activation  of  PLC-δ1 by Gi/o-coupled receptors agonists: Mediation by capacitative  Ca2+ influx in the absence of Rho activity. Am J Physiol Cell Physiol. 2004 Dec;287(6):C1679-87

Sawas AH, Pentyala SN Evaluation of lipid peroxidation in red blood cells by monitoring the uptake of sucrose and phenol red. J Applied Tox 2004 May-Jun;24(3):223-9

Sawas A, Pentyala S, Rebecchi M Binding of volatile anesthetics to serum albumin: measurements of enthalpy and solvent contributions. Biochemistry 2004 Oct 5;43(39):12675-8

Mario J. Rebecchi and Srinivas N. Pentyala: Structure, Function and Control of Phosphoinositide-Specific Phospholipase-C. Physiol Rev. 2000 Oct;80(4):1291-335.

Tall EG, Spector I, Pentyala SN, Bitter I, Rebecchi MJ. Dynamics of phosphatidylinositol 4,5-bisphosphate in actin-rich structures.  Curr Biol. 2000 Jun 15;10(12):743-746.

Srinivas Pentyala, Ki-Young Sung, Ahmed Chowdhury and Mario Rebecchi: Modulation of G-alpha subunit's GDP/GTP exchange by volatile anesthetics. European Journal of Pharmacology,384:217-226,1999.

Tieli Wang, Srinivas Pentyala, John Elliott, Louisa Dowal, Ekta Gupta, Mario Rebecchi and Suzanne Scarlata : Selective Interaction of the C2 domains of phospholipase C-b1 andbb2 with activated G_q subunits: A novel function for C2 signaling modules. Proc. Natl. Acad. Sci., 96: 7843-7846, 1999.

Tieli Wang, Srinivas Pentyala, Mario Rebecchi and Suzanne Scarlata : Differential association of the PH domains of phospholipase b and phospholipase d to lipid bilayers and the bgsubunits of G-proteins. Biochem. 38: 1517-1524, 1999.

Hod Y., Pentyala, S.N., Whyard, T., El-Magrabhi, R.: Identification and characterization of a novel protein that regulates RNA-protein interaction. J. Cell. Biochem. 72: 435-444, 1999.

Srinivas Pentyala, Daryn Moller, Ahmed Chowdhury, Ki-Young Sung and Mario Rebecchi. : Effects of inhalational anesthetics on alpha₂-adrenergic signaling in isolated platelets. Toxicol. Letts. 100: 115-120, 1998.

Pentyala, S.N., Whyard, T., Waltzer, W.C., Meek, A.G. and Hod, Y. : Androgen induction of Urokinase gene expression in LNCaP cells is dependent on their interaction with the extracellular matrix. Cancer Letts. I132: 121-126, 1998, 1998.

Srinivas N Pentyala and William B Benjamin : Effect of Oxaloacetate and phosphorylation on ATP-Citrate lyase activity. Biochemistry.34, (35) 10961-10969 (1995).

Benjamin, W. B., Pentyala, S.N., Woodgett, J. R., Hod, Y,. and Marshak, D.,The metabolism of ATP-citrate lyase and GSK-3 in the differentiating 3T3-L1 cell. Biochem. J. 300, 477-482, (1994).

Srinivas N Pentyala, Parminder J S Vig, Balwant S Sekhon and Durisala Desaiah : Effect of Carbon tetrachloride on Inositol 1,4,5-trisphosphate dependent and independent regulation of rat brain microsomal Ca2+ flux. Cell. Signal. 6, 561-567, (1994).

P.J.S.Vig, S.N.Pentyala, C.S.Chetty, B.Rajanna and D.Desaiah : Lead alters Inositol Polyphosphate Receptor activities: Protection by ATP. Pharmacol. and Toxicol. 75, 17-22, (1994).

Srinivas N Pentyala, K.Giridhar, P.Srikanth and C.S.Chetty : Permeability change in the blood brain barrier of neonate and adult rats on thiobencarb poisoning. Vet. Human. Toxicol. 35: (6) 509-511, (1993).

Srinivas N Pentyala and C.S.Chetty : Comparative study on the changes in AChE and ATPase activities in neonate and adult rat brain under thiobencarb stress. J.Appl. Toxicol. 13 (1) 39-42 (1993).

Prasada R Kodavanti, Srinivas N Pentyala, Prabhakara R Yallapragada and Durisala Desaiah : Amiodarone and Desethylamiodarone increase synaptosomal free calcium through receptor mediated channel. Arch. Pharmacol. 345:213-221 (1992).

Prasada R Kodavanti, Srinivas N Pentyala, Prabhakara R Yallapragada and Durisala Desaiah : Inhibition of cardiac calcium pump activity by cationic amphiphilic drugs. Drug. Develop. Res. 26: 49-59 (1992).

Balwant S. Sekhon, Srinivas N. Pentyala and Durisala Desaiah: In vitro effect of carbon tetrachloride on free Ca2+ movement across rat brain microsomal membranes. Transaction - Science & Engineering Alliance newsletter. 2 (1): 9-11 (1992).

Durisala Desaiah, Srinivas N Pentyala, Charles H Trottman, Parminder J S Vig, and Balwant S Sekhon : Combined effects of carbontetrachloride and chlordecone on calmodulin activity in gerbil brain. J. Toxicol. Environ. Hlth. 34 (2) 219-228 (1991).

Joseph A Cameron, Prasada R Kodavanti, Srinivas N Pentyala and Durisala Desaiah : Triorganotin inhibition of rat cardiac adenosine triphosphatases and catecholamine binding. J. Appl. Toxicol. 11 (6) 403-409 (1991).