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Protein kinase C involvement in maintenance and modulation of noradrenaline release in the mouse brain cortex
Author(s) -
Schroeder G.E.,
Kotsonis P.,
Musgrave I.F.,
Majewski H.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb17238.x
Subject(s) - protein kinase c , phorbol , protein kinase a , endocrinology , activator (genetics) , polymyxin b , biology , kinase , medicine , stimulation , chemistry , microbiology and biotechnology , biochemistry , receptor , antibiotics
1 The role of protein kinase C in the modulation of noradrenaline release was investigated in mouse cortical slices which were pre‐incubated with [ 3 H]‐noradrenaline. The aim was to investigate the hypothesis that protein kinase C is activated during high levels of transmitter release to maintain transmitter output. 2 The protein kinase C activators, phorbol myristate acetate (0.01‐0.3 μm) and to a greater extent 4β‐phorbol 12,13‐dibutyrate (0.01‐0.3 μm) significantly enhanced stimulation‐induced noradrenaline release whereas 4α‐phorbol 12,13‐dibutyrate (0.1 μm) which does not activate protein kinase C was without effect. The effect of the protein kinase C activator, phorbol myristate acetate, on noradrenaline release was attenuated by the protein kinase C inhibitor, polymyxin B (21 μm) which by itself inhibited stimulation‐induced noradrenaline release. 3 Protein kinase C was down‐regulated by 10 h exposure of the cortical slices to 4β‐phorbol 12,13‐dibutyrate (1 μm). In this case the facilitatory effect of 4β‐phorbol 12,13‐dibutyrate (0.1 μm) on noradrenaline release was abolished as was the inhibitory effect produced by polymyxin B. This indicates that polymyxin B was acting selectively at protein kinase C. 4 The inhibitory effect of polymyxin B on noradrenaline release, when expressed as a percentage of the appropriate frequency control, was constant at 1, 5 and 10 Hz. Furthermore, the ratio of release at 5 Hz to that at 10 Hz was not altered by protein kinase C down‐regulation, indicating that there is no additional effect of protein kinase C at higher stimulation frequencies. 5 When transmitter release was elevated by blocking α 2 ‐adrenoceptor auto‐inhibition with idazoxan (0.1 μ m ) or K + channels with tetraethylammonium (300 μm), the elevation in transmitter release was significantly attenuated by protein kinase C down‐regulation, suggesting an involvement of protein kinase C. 6 We conclude that protein kinase C is involved in the modulation of noradrenaline release over a wide range of stimulation frequencies, in addition to a role when noradrenaline release is elevated by presynaptic mechanisms.