Our work aims towards an increased understanding of ion channels and G protein-coupled receptors, and their regulation of neuronal activity. We focus on K channels and dopamine receptors, using electrophysiology, pharmacology, molecular biology, and theoretical-mathematical methods. The ion channels are studied with voltage clamp technique, and the dopamine receptors by recording currents from receptor-activated GIRK channels, which provide a unique time-resolved readout of receptor activity.
For the analysis of channel regulation of neuronal firing patterns, we use bifurcation theory and dynamic clamp technology, injecting currents based on real-time simulations to mimic those of ion channels, into nerve cells. We are presently developing an improved version of dynamic clamp offering increased clamp stability, aiming at using this technique on myelinated axons.
The studies will help us to understand the mechanisms of therapeutic drugs on ion channels and receptors, and the role of ion channels in conditions such as anesthesia, epilepsy, MS, and ALS. They are also of relevance for understanding disorders of the dopamine system, such as psychosis and Parkinson’s disease.
Altered action potential dynamics
Changed excitability of a pyramidal neuron (left) induced by injection of Kv channel current using the dynamic clamp technique. Native integrator dynamics (A) is changed into resonator dynamics (B) after addition of virtual computed-generated Kv channels. Resonator dynamics is characterized by reduced latency to first spike and increased after hyperpolarization as can be seen in B. Resonators are especially suited for large-scale network synchronicity.
The fast-off hypothesis revisited: A functional kinetic study of antipsychotic antagonism of the dopamine D2 receptor.
Eur Neuropsychopharmacol 2016 Mar;26(3):467-76
Density of voltage-gated potassium channels is a bifurcation parameter in pyramidal neurons.
J. Neurophysiol. 2015 Jan;113(2):537-49
Typical and atypical antipsychotics do not differ markedly in their reversibility of antagonism of the dopamine D2 receptor.
Int. J. Neuropsychopharmacol. 2014 Jan;17(1):149-55
Ion channel density regulates switches between regular and fast spiking in soma but not in axons.
PLoS Comput. Biol. 2010 Apr;6(4):e1000753
Bupivacaine blocks N-type inactivating Kv channels in the open state: no allosteric effect on inactivation kinetics.
Biophys. J. 2008 Dec;95(11):5138-52
Kristoffer Sahlholm - Postdoc
Hugo Zeberg - Postdoc
Richard Ågren - Phd Student
Georg Jomaa - Student