Prof. Dr. med. Doris Koesling, Pharmacology and Toxicology
Research Programme:
The NO/cGMP signalling cascade in the central nervous system
The NO/cGMP signalling cascade plays an important role in the central nervous system and nitric oxide (NO) has been suggested to play a role e.g. as a retrograde messenger in long-term potentiation (LTP) in the CA1 region of the hippocampus. The cGMP forming enzyme NO-sensitive guanylyl cyclase (GC) which is stimulated by NO-binding to its heme group represents the most important receptor for NO.
Two isoforms of the NO receptor exist. We generated KO mice lacking either one of the NO receptors. Results obtained in the visual cortex and hippocampus of these mice revealed that both NO receptors are required for LTP and suggest the occurrence of two NO-binding events. Analysis of the electrophysiological properties is carried out in collaboration with Thomas Mittmann's group.
Aims of forthcoming projects are:
- to study LTP in other regions of the brain to find out whether NO/cGMP signalling is involved in LTP there too
- to study LTD in order to find a general role of NO/cGMP signalling in synaptic plasticity
- to elucidate cGMP-induced functional changes occurring in the pre- and postsynaptic nerve terminal to be able to predict effects of NO/cGMP signalling
- to identify the molecular mechanisms underlying the respective changes in the pre- and postsynaptic nerve terminals.
- to perform behavioural analysis of the mice lacking the NO receptor isoforms to identify physiological correlates for the lack of LTP.
Methods
- Measurements of intracellular cGMP changes.
- Identification of the phosphodiesterase responsible for cGMP degradation.
- Western blot analysis of the members of the signalling cascade (NO synthases, NO receptor isoforms, the cGMP effector molecules)
- Studies of a possible cGMP-dependent phosphorylation of AMPA receptors with phosphor-specific antibodies
- Determination of neurotransmitter release