Activation of adenylate cyclase attenuates the hyperpolarization following single action potentials in brain noradrenergic neurons independently of protein kinase a |
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| Institution: | 1. Institute of Immunology, Faculty of Medicine, RWTH Aachen University, University Hospital, Pauwelstrasse 30, 52074 Aachen, Germany;2. Institute of Medical Statistics, Faculty of Medicine, RWTH Aachen University, University Hospital, Pauwelstrasse 30, 52074 Aachen, Germany;3. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, University Hospital, Pauwelstrasse 30, 52074 Aachen, Germany;4. Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany;5. Department of Neuroanatomy, Ludwig-Maximilians University of Munich, Pettenkoferstrasse 11, 80336 Munich, Germany |
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| Abstract: | Afterhyperpolarizations that follow action potentials are a prominent mechanism for the control of neuronal excitability. Such afterhyperpolarizations in many neurons are modulated by a variety of second messenger systems. Here, we examined the regulation of afterhyperpolarizations in noradrenergic locus coeruleus neurons by the adenylate cyclase system. Although superfusion of the adenylate cyclase activator, forskolin, had no effect on hyperpolarizations following trains of action potentials, both forskolin and a membrane permeable analog of cyclic AMP, 8-bromo-cyclic AMP, attenuated the amplitude of afterhyperpolarizations which followed single action potentials of locus coeruleus neurons recorded intracellularly in brain slices. In contrast, superfusion of 1,9-dideoxyforskolin, the forskolin analog that does not activate adenylate cyclase, had no effect on these single action potential afterhyperpolarizations. Co-application of a protein kinase inhibitor (H8, KT5720, staurosporin or Rp-cAMPS) with either forskolin or 8-bromo-cyclic AMP failed to block the reduction of afterhyperpolarization amplitude, but blocked the cyclic AMP-dependent enhancement of opiate responses in the same locus coeruleus neurons. Furthermore, application of a membrane permeable analog of 5'-AMP, 8-bromo-5'-AMP, the cyclic AMP metabolite that does not activate a protein kinase, potently reduced the amplitudes of single action potential afterhyperpolarizations. The afterhyperpolarization amplitude was also reduced in locus coeruleus neurons taken from chronically morphine-treated rats, a treatment known to increase adenylate cyclase activity.These results indicate that elevation of intracellular cyclic AMP or 5'-AMP reduces the single action potential afterhyperpolarization in locus coeruleus neurons. This action may be mediated through a mechanism independent of protein kinase activation. |
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