The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig

Previous studies have demonstrated that vestibular compensation, the proces s of behavioural recovery which occurs following unilateral deafferentation of the vestibular labyrinth (UVD), is correlated with changes in in vitro phosphorylation of various protein substrates in the brainstem vestibular n ucleus complex (VNC). The aim of the present study was to investigate the p ossible causal relationship between protein kinase activity and the inducti on of the vestibular compensation process, by delivering inhibitors of prot ein kinase C (PKC) or Ca2+/calmodulin-dependent kinase II (CaMKII) into the ipsilateral VNC at the time of the UVD and determining their effects on th ree static symptoms of UVD, spontaneous nystagmus (SN), yaw head tilt (YHT) and roll head tilt (RHT) in guinea pigs. Infusion of the PKC inhibitor, 3- [1-( 3-dimethylaminopropyl)-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5 -dione, HCl (bisindolylmaleimide I, HCl/GF 109203X, HCl) ('Bis I'), at a co ncentration of 5 or 50 muM, significantly increased SN frequency at the ear liest time points (6 and 8 h post-UVD) compared to vehicle controls and the less selective analogue, 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (bisindo lylmaleimide V) ('Bis V'). However, the compensation of YHT and RHT was una ffected by the PKC inhibitor. By contrast, the cell-permeable CaMKII inhibi tor, myristoylated autocamtide-2 related inhibitory peptide (N-Myr-Lys-Lys- Ala-Leu-Arg-Arg-Gin-Glu-Ala-Val-Asp-Ala-Leu-OH) ('myr-AIP') or the cell-imp ermeable analogue, autocamtide-2 related inhibitory peptide (N-Lys-Lys-Ala- Leu-Arg-Arg-Cln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('AIP'), failed to alter the co mpensation of SN, YHT or RHT at any dose compared to vehicle controls. Thes e results implicate PKC-, but not CaMKII-, signal transduction pathways in the initiation of SN compensation in guinea pig. (C) 2000 Elsevier Science B.V. All rights reserved.