Research Field: Signaling Mechanisms; Endothelins, Muscarinic, NMDA Receptors
Research Activity:
- Endothelin Receptors: The endothelins (ETs) are potent vasoactive peptides that appear to be involved in diverse biological actions, for example contraction, neuromodulation and neurotransmission, as well as in various pathophysiological conditions such as renal and heart failure. The diversity of actions of ETs as we suggested may be explained in terms of (i) the existence of several receptor subtypes and (ii) the activation of different signal transduction pathways. Our research effort in this intensively studied field, will focus on structural aspects, receptor heterogeneity, coupling of receptors to G-proteins, and signal transduction mechanisms mediated by the activation of ET-receptors. We believe that the diversity of action of endothelins will serve as the basis on which future therapeutic approaches will be designed.
- Muscarinic Acelylcholine Receptors: We have conducted detailed and comprehensive studies on the muscarinic receptor system, which plays a major role in learning and memory, as well as in pathophysiological conditions (e.g. Alzheimer’s disease). Here we shall cite four aspects which serve as the basis for future studies to be conducted : (i) The demonstration that the m1 muscarinic receptor subtype may function as an agonist dependent growth factor. Is it subtype specific? (ii) The demonstration that activation of muscarinic receptors by agonists inhibits apoptotic death of growth factor- deprived PC12M1 cells; this protective effect was observed in both proliferative and neuronal cells. (iii) The identification of muscarinic involvement in the regulation of gonadotropin releasing hormone (GnRH); the suggestion was made that this muscarinic-mediated stimulation of GnRH release stems from cross-talk between the muscarinic and adrenergic receptors. (iv) The demonstration of the role of membrane potential in transducing signals via the muscarinic receptors in excitable cells.
- The N-Methyl-D-Aspartate (NMDA) receptors: The NMDA class of excitatory amino acid receptors plays an important role in neuronal plasticity and memory acquisition, as well as in pathological conditions that lead to neuronal death and to epileptic seizures. Our work centered on NMDA receptor structure - function indicating the existence of receptor heterogeneity in various brain regions; These studies lead to the development of various blockers with the specific aim of eliminating abnormal behavior mediated via agonist binding to the NMDA receptors . In particular, one has to cite our contribution to the introduction of a non-psychoactive cannabinoid (code name:HU-211), which exhibits pharmacological autonomic and behavioral effects typically caused by NMDA receptor antagonist. The lack of psychoactive effects is remarkable, since this feature has long been sought for (without much success) in the design of drug inhibitors. Following this discovery, this therapeutic approach as well as structure - activity relationships of the various receptors are being explored.
