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Molecular mechanisms of signalling bias at muscarinic receptors

Laboratory of Neurochemistry

PhD project: Molecular mechanisms of signalling bias at muscarinic receptors

Muscarinic acetylcholine receptors are G-protein coupled receptors (GPCRs) located in the plasma membrane of many cell types of various tissues. These receptors mediate extracellular to intracellular signalling. Alterations in signalling via muscarinic receptors play an important role in a variety of neurological and psychiatric disorders, e.g. Alzheimer's disease, schizophrenia, and also in other internal diseases, e.g. asthma and overactive bladder. A biased agonist is a ligand which stabilizes a particular active conformation of a receptor, thus stimulating some responses but not others. Biased agonists might represent a novel and uniquely effective type of therapeutic agent with reduced side-effects. Several lines of evidence suggest that some muscarinic agonists although they bind with the same affinity to all subtypes of muscarinic receptor activate individual subtypes to different extent and display signalling bias. Understanding of the molecular mechanisms of signalling bias at muscarinic receptors may facilitate development of desired functionally-selective antagonists and agonists.

Candidate’s profile (requirements):

MD or MSc or equivalent degree in physiology, cellular biology, biochemistry, molecular biology or pharmacology. Practice at laboratory of biochemistry, pharmacology or molecular biology.

Supervisor: Jan Jakubík, Ph.D. (jan.jakubik@fgu.cas.cz)

Relevant publications:

R.M. Eglen, Overview of muscarinic receptor subtypes, in: A.D. Fryer, Arthur Christopoulos, N.M. Nathanson (Eds.), Handb Exp Pharmacol, Springer 2012: pp. 3–28.
T. Kenakin, A. Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact, Nat Rev Drug Discov. 12 (2013) 205–216.
A. Randáková, E. Dolejší, V. Rudajev, P. Zimčík, V. Doležal, E.E. El-Fakahany, J. Jakubík, Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms, Pharmacol Res. 97 (2015) 27–39.
Randáková A, Nelic D, Ungerová D, Nwokoye P, Su Q, Doležal V, El-Fakahany EE, Boulos J, and Jakubík J, Novel M2 -selective, Gi -biased agonists of muscarinic acetylcholine receptors. Br J Pharmacol (2020) doi: 10.1111/bph.14970.