ION CHANNELS AND TRANSPORTERS AS
MOLECULAR DRUG TARGETS
and the
Pharma &Food Lecture Series (580006 SE) are pleased to invite you to the following lecture
“Allopharmacology: GPCR signaling to Ion Channels”
by Prof. Diomedes E. LOGOTHETIS, PhD
Professor of Pharmaceutical Sciences, School of Pharmacy
Bouvé College of Health Sciences, Northeastern Univ., Boston, MA
Department of Pharmaceutical Sciences
on: Thursday, May 11, 2023, 11:30am
at: UZA 2, Josef Holaubek-Platz 2, 1090 Vienna, Lecture Hall 5 (HS 5)
Host: Assoz.Prof. Anna Weinzinger
ABSTRACT: G protein gated inwardly rectifying K+ (GIRK) channels are coupled to G protein coupled receptors (GPCRs) via pertussis toxin-sensitive G proteins. Like all 16 members of the inwardly rectifying K+ (Kir) channels, they interact with the inner membrane leaflet phospholipid phosphatidylinositol bis-phosphate (PIP2) to determine their gating (opening and closing of the channel gates). GIRKs unlike most other Kirs, interact weakly with PIP2, and need help from channel activators such as Gbg, [Na+]i, alcohol, cholesterol and drugs to strengthen these interactions and open the channel gates. Atomic resolution structures reveal two gates in series: the membrane (helix bundle crossing - HBC) and the cytosolic (G-loop). Molecular Dynamics (MD) simulations reveal the mechanism by which the interactions of the openers at their binding sites lead to allosteric stabilization of the open state by PIP2. Combinations of openers that act on distinct sites (e.g., Gbg vs. Na+, Gbg vs. drugs, alcohol vs. drugs) synergize in activating the channel by controlling predominantly distinct gates. Targeting specific GIRK isoforms and homomeric or heteromeric GPCRs expressed in specific tissues as well as using combinations of drugs acting directly on GIRKs amplifies through synergism producing astonishing effects through GIRKs, like complete analgesia with cocktails of drugs targeting (GPCRs and GIRK channels) that when applied by themselves are minimally (<10%) activating. Atomic resolution structures of GIRK GEMMAs (GPCR-Effector Macromolecular Membrane Assemblies) are likely to occupy us in the next decade, as we aim to decipher basic mechanisms of allosteric coupling within the GEMMAs, induced by drugs acting on GPCRs or the Channels (Allosteric pharmacology) and to exploit this knowledge for structure-based drug design.
RESEARCH INTERESTS:
• Phosphoinositide signaling to ion channels and membrane proteins
• Heteromeric G protein coupled receptor (GPCR) signaling in health and disease
• Mechanisms of action of small molecule ligands on ion channels and GPCRs
More information on the website of the lecturer.
