Boopathi Ettickan, PhD
Philadelphia, PA 19107
(215) 503-5731 fax
Research and Clinical Interests
G-protein-coupled receptors (GPCR) mediated signaling smooth muscle.
Altered contractile-protein expression and increased smooth-muscle cell (SMC) proliferation are characteristics of various disease conditions including hypertension, asthma, and intestine and bladder pathologies. It is well known that smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain kinase, and the latter is achieved partly by the inhibition of myosin phosphatase. Calcium released by the intracellular stores binds to calmodulin, and Ca-CaM complex activates MLC kinase that subsequently phosphorylates MLC. The small GTPase RhoA, Rho-associated kinase (the target of RhoA), and Protein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) participate in the calcium sensitization mechanism. The cellular activity of myosin light chain phosphatase (MLCP) determines the agonist-induced force development in smooth muscle. Both calcium- and Ca2+ sensitization- mediated contraction plays role in G-protein signaling during smooth-muscle contraction. The long-term goals of this project are to elucidate the role of GPCR mediated signaling in smooth muscle contraction and proliferation under pathophysiological conditions.
Mitochondria and smooth muscle contraction: Role of desmin cytoskeleton protein.
The second major area of investigation is to understand the role of cytoskeleton proteins, desmin and vimentin in smooth muscle contraction and mitochondrial respiration. In recent years research has shown that desmin and vimentin are involved in signaling pathways and they are the primary factors in facilitating the mechanotransduction. In addition, desmin and vimentin cytoskeleton interacts with mitochondria and possibly modulates respiration. Adenosine triphosphate (ATP) and phosphocreatine are the immediate substrates for processes involved in muscle contraction and relaxation, Ca2+ handling, and phosphorylation. Voltage-dependent anion channel (VDAC) located at the mitochondrial outer membrane play a crucial role in regulating the metabolic and energetic functions of mitochondria and are primarily responsible for the ATP/ADP flux across the outer mitochondrial membrane. The VDAC interact with adenine nucleotide translocase (ANT) to control the mitochondrial membrane permeability to ADP. Mitochondrial desmin and vimentin interacts with the VDAC and this interaction disrupts VDAC/MtCK/ANT complex formation, thereby inhibiting the ATP synthesis and promoting ROS production under pathological conditions in smooth muscle. My long term goal of this project is to elucidate our understanding of the mechanism by which desmin and vimentin induces mitochondrial and muscle dysfunction under pathological conditions in smooth muscle. This could lead to novel molecular targets for therapeutic interventions in smooth muscle pathologies.
Most Recent Peer-Reviewed Publications
- RB loss promotes prostate cancer metastasis
- Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: Role of microRNA-133a
- The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness
- Mechanical stretch upregulates proteins involved in Ca<sup>2+</sup> sensitization in urinary bladder smooth muscle hypertrophy
- Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle
- GATA-6 and NF-κB activate CPI-17 gene transcription and regulate ca2+ sensitization of smooth muscle contraction
- Inherent sex-dependent regulation of human hepatic CYP3A5
- Regulation of miR106b cluster through the RB pathway: Mechanismand functional targets
- Generation of a human urinary bladder smooth muscle cell line
- Intrinsic sexually dimorphic expression of the principal human CYP3A4 correlated with suboptimal activation of GH/glucocorticoid-dependent transcriptional pathways in men
- Transcriptional repression of caveolin-1 (CAV1) gene expression by GATA-6 in bladder smooth muscle hypertrophy in mice and human beings
- Alterations in Caveolin Expression and Ultrastructure After Bladder Smooth Muscle Hypertrophy
- Bimodal Protein Targeting through Activation of Cryptic Mitochondrial Targeting Signals by an Inducible Cytosolic Endoprotease
- Role of protein kinase C-mediated protein phosphorylation in mitochondrial translocation of mouse CYP1A1, which contains a non-canonical targeting signal
- Regulation of murine cytochrome c oxidase Vb gene expression during myogenesis: YY-1 and heterogeneous nuclear ribonucleoprotein D-like protein (JKTBP1) reciprocally regulate transcription activity by physical interaction with the BERF-1/ZBP-89 factor
- Accumulation of mitochondrial P450MT2, NH
2-terminal truncated cytochrome P4501A1 in rat brain during chronic treatment with β-naphthoflavone. A role in the metabolism of neuroactive drugs