Molecular and Cellular Pharmacology
Jagtvej 160, København Ø
Primary fields of research
Throughout my academic career, I have been focusing on the regulation of vascular tone in health and disease (diabetes type I & II, stroke, hypertension, congestive heart failure, migraine and age-related changes).
Coronary arteries are densely innervated by sensory nerve endings containing calcitonin gene-related peptide (CGRP). CGRP is a potent naturally occurring 37 amino acid vasodilatory neuropeptide, which is released from the perivascular sensory nerve endings in the wall of flow regulating intramural coronary arteries during hypoxia and by low pH levels in the myocardium, thus suggesting a vasodilatory role under ischemic conditions.
Receptor subtypes for CGRP, the intracellular signaling pathways and the mechanism behind CGRP-induced desensitization and neuronal reuptake are still under investigation in both resistance and conductance arteries of different species including human. So far, these studies clearly demonstrate a higher CGRP receptor density in resistance arteries (internal lumen diameter < 200 µm) compared to larger conductance arteries (internal lumen diameter > 200 µm), indicating that receptor distribution, calcium handling, ion channels and second messengers may be finely adjusted within the circulatory system, probably reflecting the physiological demands on the vascular segments.
CGRP receptor consists of three components, calcitonin receptor-like receptor (CLR), a specific chaperone called receptor activity modifying protein 1 (RAMP1) and receptor component protein (RCP). A novel family of chaperone proteins, called RAMPs (RAMP1, RAMP2 and RAMP3) were identified as proteins escorting CLR to the plasma membrane to generate either CGRP (when associated with RAMP1) or adrenomedullin receptors (when associated with RAMP2 or RAMP3). CLR belongs to class B of the G protein-coupled receptor (GPCR) family and is linked to Gs protein. It was recently reported that the small non-peptide CGRP receptor antagonists (olcegepant and telcagepant) act by blocking access of CGRP to the peptide-binding cleft at the interface of CLR and RAMP1.
Our recent studies on isolated human subcutaneous arteries clearly show that key components of the CGRP receptor (CLR and RAMP1) are located on both smooth muscle and endothelial cells. Despite the presence of functional endothelium in these human vessels (verified by functional studies using carbachol, substance P and bradykinin), the contribution of the endothelium to CGRP-induced vasodilation seems to be insignificant. Perhaps, the CGRP receptors located on the endothelium have different biological effects than being directly involved in the vasomotor control or the density of CGRP receptors is significantly higher on smooth muscle cells compared with the endothelium. Recent studies have shown that CGRP acts as a pro-angiogenic growth factor by increasing the secretion of vascular endothelial growth factor and expression of focal adhesion kinase, thereby contributing to remodeling.
In addition, our most recent studies on CGRP receptor signaling show synergism between smooth muscle Kv7.4/7.5 channels and CGRP-induced vasodilation in isolated human subcutaneous arteries so that CGRP-induced vasodilation becomes more potent and prolonged. However, XE-991 dihydrochloride (a non-selective blocker of KCNQ channels) was not able to block the CGRP-induced vasodilation in these vessels. Furthermore, our recent studies in human subcutaneous arteries using 10 microM Gallein indicate involvement of Beta-gamma subunit of G-protein in intracellular signaling pathway leading to vasodilation perhaps via activation of potassium channels.
These studies will shed light on the complexity of CGRP receptor pharmacology as well as its complex signaling pathway, thereby helping us understand its physiology as well as its role under different circulatory complications such as stroke, ischemia, hypertension and migraine.
Over 20 years of teaching experience in the field of Pharmacology covering a wide range of areas: Cardiovascular Pharmacology, Endocrinology (diabetes and obesity), Receptor Pharmacology and Intracellular Signaling Pathways, and Pharmacokinetics and –dynamics.
Supervision of students:
Supervised over 60 Master Thesis students and 15 PhD-students.
Member of didactic committee at the Faculty of Pharmaceutical Sciences and Chairman of the teaching committee at the Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen: from January 2008 - March 2012
August 2012 - May 2019: Member of the committee for Research and Innovation (FIU) at the Dept. of Drug Design and Pharmacology, University of Copenhagen.
January 2017 - December 2019: Course director for "Organ pharmacology", Bachelor course for Pharmacy students at the 4th semester.
Pedagogic course for PhD-students (November 1996, 30 lectures distributed over 3 days): Teaching and learning, Royal Danish School of Pharmacy, Instructor: Associate Professor, Arne Jakobsen.
23 august 2001 - 1 september 2002: Pedagogic training for Assistant Professors at Danish Universities, The Danish University of Pharmaceutical Sciences. Holder of certificate for Higher Education Teaching and Teaching Practice (signed by the Rector, Prof. Sven Frøkjær 11. April 2003).
Course in supervision of PhD-students: 8th and 9th of September 2009 and 27th of October 2009: PUMA course in supervision of PhD-students at the University of Copenhagen.
Course for Department Supervisors: 15th of April, 2011 at 9:00-16:00, Øster Voldgade 3 (the observatory), 1350 Copenhagen, Organizers: Camilla Rump and Lars Ulriksen.
Fields of interest
1- Cardiovascular and neurovascular Pharmacology: Hypertension, Diabetes, Obesity, Stroke, Cardiac pain (silent ischemia), Migraine
2- G-protein-coupled receptor pharmacology, intracellular calcium handling and intracellular signaling pathways
3- Fluorescence microscopy and measurements of intracellular calcium concentration
4- Pharmacokinetics and pharmakodynamics (PK-PD studies)