sfs1@columbia.edu

PROFESSOR OF PHARMACOLOGY

The research in my laboratory primarily focuses on catecholamine actions at a₁- and b-adrenergic receptors in the heart.  Our aims are to define the biochemical signal transduction pathways and ionic mechanisms activated by these receptors and determine their contributions to changes in cardiac cell function.  The studies combine biochemical and molecular techniques with measurements of cytosolic calcium and pH (using fluorescence microscopy with ion sensitive dyes) and simultaneous assessments of single cardiac myocytes contractile motion (using a video edge detection system).  The model systems under investigation are designed to examine changes in cardiomyocyte responsiveness that accompany development, sympathetic innervation, and/or pathologic injury of the heart.

Recent studies of the developmental changes in a₁-adrenergic responsiveness have focused on the role of a critical component of the a₁-receptor signaling pathway, the distinct molecular isoforms of protein kinase C (PKC).  We have detected dramatic age-dependent differences in PKC isoform expression and demonstrated that thyroid hormone modulates PKC expression in a manner that suggests that it might function as a developmental regulator of this enzyme.  We have established that one particular isoform of PKC (PKC-e) regulates intracellular calcium and growth-related pathways and we have demonstrated that this isoform is activated when myocytes are deprived of oxygen.  The functional consequences of developmental and/or disease associated changes in PKC isoform expression and action are a major ongoing focus of research in the laboratory.

Other studies have revealed developmental differences in b-adrenergic receptor subtype action in cardiomyocytes.  Specifically, b₁-adrenergic receptors (the predominant subtype in both neonatal and adult ventricular myocytes), elevate intracellular cAMP, and induce protein kinase A-dependent changes in contractile function in both neonatal and adult ventricular myocytes.  However, b₂-adrenergic receptors (which assume greater importance as a mechanism for the inotropic support of the failing, aged, or transplanted heart) follow distinct pathways in neonatal and adult ventricular myocytes.  The pathway linking b₂-adrenergic receptors to cAMP-dependent changes in contractile function is expressed only in the neonate.  In contrast, we recently demonstrated that b₂-adrenergic receptors increase the contractile performance of adult myocytes via a cAMP-independent mechanism that involves activation of a bicarbonate-dependent pH-regulatory mechanism.  This mechanism induces intracellular alkalinization which would enhance the sensitivity of the contractile apparatus to calcium.  The goals of future research in this area will be to identify the mechanism(s) that regulate b₂-receptors-adenylyl cyclase enzyme interactions and to investigate b-adrenergic receptor subtype signaling in the diseased, failing heart.

Selected Publications:

1. Sabri A, Pak E, Alcott SA, Wilson BA and Steinberg SF:  Coupling function of endogenous a₁- and b-adrenergic receptors in mouse cardiomyocytes.  Circ. Res.  86:1047-1053, 2000. Abstract PDF File

2. Sabri A, Muske G, Zhang HL, Pak E, Darrow A, Andrade-Gordon P and Steinberg SF:  The signaling properties and functions of two distinct cardiomyocyte protease-activated receptors.  Circ. Res.  86:1054-1061, 2000. Abstract PDF File

3. Rybin VO, Xu X, Lisanti MP and Steinberg SF: Differential targeting of b-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae: A mechanism to functionally regulate the cAMP signaling pathway.  J. Biol. Chem.  275:41447-41457, 2000. Abstract PDF File

4. Sabri AK, Wilson BA and Steinberg SF: Dual actions of the Ga_q agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility. Circ. Res. 90:850-857, 2002. Abstract PDF File

5. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch, E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HYM, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg, SF, Wymann MP, Backx PH and Penninger JM: Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737-749, 2002. Abstract PDF File

6. Xiang Y, Rybin VO, Steinberg SF and Kobilka B: Caveolar localization dictates physiological signaling of b₂-adrenergic receptors in neonatal cardic myocytes. J. Biol. Chem. 277:34280-34286, 2002. Abstract PDF File

7. Sabri AK, Short J, Guo J and Steinberg SF: Protease-activated receptor-1-mediated DNA synthesis in cardiac fibroblasts is via epidermal growth factor receptor transactivation: Distinct PAR-1 signaling pathways in cardiac fibroblasts and cardiomyocytes. Circ. Res. 91:532-539, 2002. Abstract PDF File

Schematic diagram depicting the potential sites for protein kinase C- dependent phosphorylation and modulation of cardiac myocyte contractile function. SL = sarolemma; SR = sarcoplasmic reticulum; lca = calcium channel; Na/H = Na/H exchanger; RyR = ryanodine receptor.