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Molecular mechanisms of membrane cholesterol effects on function of muscarinic receptors

PhD project:  Molecular mechanisms of membrane cholesterol effects on function of 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.

Cholesterol has been found to co-crystallize with a number of GPCRs.  Our current experiments show that membrane cholesterol specifically binds to muscarinc receptor and slows down their activation. Aim of the project is to delineate the molecular mechanisms of cholesterol action at muscarinic receptors and to identify putative differences among subtypes of muscarinic receptors

 

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.

 

Relavant 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.

G. Gimpl, Interaction of G protein coupled receptors and cholesterol, Chem Phys Lipids. 199 (2016) 61–73.

P. Michal, E.E. El-Fakahany, V. Doležal, Changes in Membrane Cholesterol Differentially Influence Preferential and Non-preferential Signaling of the M1 and M3 Muscarinic Acetylcholine Receptors, Neurochem Res. 40 (2014) 2068–2077.

Randáková, A., Dolejší, E., Rudajev, V., Zimčík, P., Doležal, V., El-Fakahany, E. E., & Jakubík, J. (2018). Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline. Neuropharmacology, 133, 129–144.

M. Manna, M. Niemelä, J. Tynkkynen, M. Javanainen, W. Kulig, D.J. Müller, T. Rog, I. Vattulainen, Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol, Elife. 5 (2016) 1–21.

 

Supervisor: Jan Jakubík PhD

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