Fernando A. González
Professor
Phone
(787) 764-0000 ext. 2437
fgonzal hpcf upr edu
Education
Ph.D., Cornell University (1989)Â
Research interests
Biochemistry and Molecular Biology: Signal Transduction by P2 Nucleotide Receptors and Cell Growth Regulation.
Research focus
P2 Nucleotide Receptors. A long range goal of our research is to increase our understanding of the signal transduction by P2 purinoceptors (receptors for extracellular ATP). The recognition of effects of extracellular purines on mammalian cells can be dated back to the 1920's when Drury and Szent- Györgyi found that the adenosine content of extracts from brain, kidney, heart muscle and spleen "disturbed the cardiac rhythm in a constant and definite manner." Today, it is recognized that the nucleotide neurotransmitters adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) mediate many biological responses in a variety of cellular systems by activation of specific cell surface P2 receptors.
Extracellular nucleotides activate P2Y2 receptors that modulate a variety of important biological processes, such as ion secretion, cellular growth, and vasodilatation, among others. UTP (a P2Y2 receptor agonist) has been shown to induce calcium-dependent anion secretion in airway epithelial cells expressing a defective cystic fibrosis transmembrane conductance regulator, a cAMP-dependent chloride channel. This observation suggests that nucleotides may be efficacious in the treatment of cystic fibrosis. One potential limitation of this therapy is that prolonged exposure to nucleotides causes desensitization of the P2Y2 receptor leading to receptor sequestration and downregulation. Considering the therapeutic potential for P2Y2 receptor activation in vivo, we attempt to understand the molecular mechanisms underlying receptor desensitization. Our results suggest that desensitization is caused by phosphorylation of amino acid residues in the intracellular C-terminal domain of the receptor. Currently we apply molecular, biochemical and pharmacological approaches to study the mechanisms of desensitization of a recombinant P2Y2 receptor expressed in human 1321N1J astrocytoma cells that lack endogenous nucleotide receptors. This transfection system is being used to express a variety of P2Y2 nucleotide receptor constructs (e.g., deletion and point mutants) to identify the specific phosphorylation sites and protein kinases that regulate agonist-induced desensitization and sequestration (i.e., uncoupling and internalization).
In addition, we are interested in understanding the structure, function and regulation of the P2Y2 and P2X7 nucleotide receptors of promonocytic human U937 cells during inflammatory activation and differentiation. Our research is focused on the identification of the P2 receptor subtype that mediates each of the nucleotide-induced effects (i.e., activation of ion channels, calcium mobilization, protein kinase cascades, pore formation, apoptosis, and receptor desensitization, sequestration and down-regulation) and the elucidation of the relationships between these responses. Furthermore, the structural determinants of the P2 receptor subtypes that are required for the functional responses is being investigated. With this research we hope to provide new insight into the molecular basis for the diverse effects of nucleotides in the immune system, information that will surely impact our ability to regulate inflammation via pharmacotherapy.
Bioactive Agents. The effect of novel bioactive compounds on cell proliferation and the molecular basis for their action is of interest to us. We have elucidated the molecular basis for the bioactivity of a family of benzazolo quinolinium DNA intercalators and the relationship of that activity to DNA binding and topoisomerase II inhibition. Currently we are investigating the structure-activity relationship in a family of cytotoxic Pt(II) complexes and their interaction with DNA.