4 ECTS credits
120 h study time
Offer 1 with catalog number 4007985ENR for all students in the 2nd semester at a (E) Master - advanced level.
This course comprises the following chapters:
1. Introduction and definition of a “chemical mediator”
This first chapter deals with signaling molecules, basic approaches to study drug-receptor interactions and the structure and function of receptors. In the first chapter of this part signaling molecules (denoted as ‘chemical mediators’) are divided according to their mode of transmission (hormones, neurotransmitters) and according to their hydrophobicity (hydrophobic hormones which pass the cell membrane/ hydrophilic/large signaling molecules whose receptors are at the outside of the plasma membrane).
2. Chemical mediators and their receptors
The receptors for chemical mediators are divided in the ways they trigger the cell response (activation of G proteins, endogenous phosphorylation, opening of ion channels).
3. Ligand-gated ion channels
This chapter deals with ligand mediated ion channels. With two typical examples the action mechanism of these receptors is explained. It concerns nicotinic acetylcholine receptor that operate the opening of sodium channels involved in the contraction of skeletal muscles and the glutamate and GABA mediated ion channels that are involved in rapid signal transduction in neurons.
4. G-protein coupled receptors
This chapter deals with G-protein coupled receptors. They represent a very large family of plasma membrane receptors that are involved in a very broad range of (patho)-physiological processes. It might therefore not surprise that about half of all the known commercial medicines exert their effects via these receptors. This chapter will explain the general mechanism of signal transduction of these receptors as well as their classification on basis of their structure/amino acid sequence. It also deals with widely used technical approaches to investigate the interaction between signaling molecules (and their synthetic analogues: agonists and antagonists) and their receptors.
5. Growth factor receptors
The next category of receptors are the growth factor or tyrosin kinase receptors. The binding of their ligands i.e. growth factors activates their intrinsic property of endogenous phosphorylation. As their name indicates, the binding of these ligands are involved in the regulation of cell growth and division.
6. Steroïd receptors
The last category of receptors are located intracellularly. They mainly recognize steroid hormones, which are apolar mediators that are able to cross the plasma membrane barrier.
7. Quantitative aspects : Radioligand receptor binding
This part deals with:
- Definition of the concepts of receptor activation
- Quantitative aspects of radioligand binding (three basic experiment types)
- Saturation binding experiments
- Competition binding
- Kinetics
8. Quantitative aspects : Functional experiments
Subsequently typical functional experiments for GPCR and the corresponding quantitative aspects will be discussed (agonist concentration-effect curves …). Attention will also be paid to concepts such as partial and inverse agonists, intrinsic activity, amplification, spare receptors … This chapter will pay attention to the complex relation between ligand-receptor binding and the measured response such as the activation of G-proteins, formation of ‘second messengers’ and tissue effects (for instance contraction of a muscle). It will deal with the major models/theories that describe and/or explain this relation. They include (i) the linear model, (ii) the ‘non-linear model’ or ‘transducer’ model, (iii) the ‘one site two-state model’, (iv) the allosteric ternary complex model’.
9. Receptor antagonists and modulators
10. Receptor desensitization
These chapters describe by which mechanism synthetic antagonists can modulate and/or inhibit ligand mediated effects. It will deal with classical competitive antagonists, competitive ‘insurmountable’ antagonists, ‘allosteric modulators’, ‘allosteric antagonists’, ‘inverse agonists’ and functional antagonists. Subsequently the molecular mechanisms will be dealt that disrupt the agonist response. It concerns mechanisms of receptor phosphorylation, desensitization and internalization.
11. Biased ligands
Originally it was thought that natural and synthetic agonists of a particular receptors induced the same cellular and biochemical responses. However, relatively recently it emerged that different ligand for one receptors can display selectivity to induce particular signal transduction pathways. In this chapter will be explained how this functional selectivity can be analyzed and whether certain ligand can be described as ‘biased ligands’.
12. Receptor oligomerization
In recent investigations it appeared that G-protein coupled receptor can occur as di- or oligomers. In this chapter will be discussed how this phenomenon can be demonstrated by recent molecular and biophysical techniques. It will also deal with the possible important consequences this can have for current molecular pharmacology.
13. The renin-angiotensin system
This chapter deals with the renin-angiotensin system in which G-protein coupled receptor play a key role. Before explaining this hormonal system a short overview is provided of the physiological regulation of the blood flow and pressure by the para- and ortho-sympathetic nervous system. The central messenger of the renin-angiotensin system is the peptide angiotensin II which has prominent role in the regulation of blood pressure. By binding to and activation of GPCR, this peptide elicits a cascade of cellular effects that result in an increased blood pressure. Therefore extensive research is carried out to develop selective antagonists of these receptors. These receptors will serve as an example to illustrate a number of pharmacological and molecular aspects of this course. It deals with (i) the different receptors of the renin-angiotensin system and their signal transduction pathways (ii) the mechanism of angiotensin II type 1 receptor antagonists and (iii) the molecular activation-mechanism of this receptor.
14. Free fatty acid receptors
While classically G-protein coupled receptors recognize hormones and neurotransmitters, it appears that intermediates of the carbohydrate and lipid metabolism are also ligands for these receptors. In this chapter we will discuss the receptors for free fatty acids. These receptors are involved in the regulation of glucose homeostasis and can therefore be considered as potential targets in the development of anti-diabetic medicines. Their working mechanism will be compared with that of current therapeutic approaches
15. Practical
The practical will complement and improve the understanding the theoretical concepts of this course. It is mandatory to follow this practical. Attention will be paid to the measurement of molecules involved in signal transduction. This can encompass radioligand binding to cell lines that express recombinant G-protein coupled receptors. In the same cell line agonist mediated activation of these receptors will be measured, such as the measurement of intracellular calcium release will be monitored.
The course material comprises the powerpoint presentations available on the learning platform.
The general aim of the course is to provide the student insight in the domain of Molecular Pharmacology. The acquired knowledge during this course is useful in a research-oriented career. It provides the bio-engineers and biologists the basic knowledge to perform pre-clinical research and to function within multi-disciplinary teams in the pharmaceutical industry
Specific competencies:
Understand the meaning and content of pharmacological concepts.
Capable of handling in an independent and critical way of pharmacological knowledge
Use the acquired knowledge in the course to understand and critically read scientific publications in the domain of molecular pharmacology
During the lectures an active attitude is encouraged by which the theoretical knowledge can be applied in concrete examples
To be able to present orally in a short time period the essentials (aims, methods, results, discussion) of a scientific publication.
To have an opinion with relation to the discussion, interpretation and conclusions in a scientific publication
Apply the theoretical knowledge of the lectures during the practicals. For example: the calculation and interpretation of the binding properties of a radioligand on basis of self-produced data during the practicals.
Cooperate in a constructive way with fellow students in the processing and reporting of experimental data.
The final grade is composed based on the following categories:
Oral Exam determines 67% of the final mark.
PRAC Report determines 33% of the final mark.
Within the Oral Exam category, the following assignments need to be completed:
Within the PRAC Report category, the following assignments need to be completed:
Oral exam
The oral exam of this course will consist of two parts it encompasses 2/3 of the points:
Part 1: This part involves the discussion of a previously provided scientific article in the domain of the molecular pharmacology. The exam comprises a short (about 5 min) presentation by the student of this article which deals with the aim, methodology, results and conclusion(s). Subsequently the lecturer asks questions to assess the insight of the student in the related concepts. This part will last between 20 and 25 min.
Part 2: A half hour before the oral exam the lecturer provides a general question related to the concepts presented during the lessons. The student discusses and answers this question and for this part will last between 20 and 25 min.
The exam is open book, so that the student is allowed to use all the information provided in the powerpoint slides of this course.
Evaluation:
The summative evaluation comprises both the oral exam as well as the practical.
2/3 of the points are given on the oral exam.
1/3 of the points are given on the practical. In this respect the students are asked to write a practical report which includes: introduction, objective(s), used techniques, analysis and discussion of the results and conclusion(s).
Participation in the practical is obligatory. When there is no justified absence the mention “AFW” will be given as the final mark of the complete course. The practical cannot be carried out in the second session and takes place in the place and dates mentioned in the lectures time-schedule and also announced in the learning platform Canvas.
This offer is part of the following study plans:
Master of Bioengineering Sciences: Cell and Gene Biotechnology: Medical Biotechnology (only offered in Dutch)