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The Effects of Protein Kinase C and Calmodulin Kinase II Inhibitors on Vestibular Compensation in the Guinea Pig

The Effects of Protein Kinase C and Calmodulin Kinase II Inhibitors on Vestibular Compensation in the Guinea Pig

A J Sansom, P F Smith, C L Darlington, R Laverty

Brain Res. 2000 Nov 3;882(1-2):45-54.

PMID: 11056183

Abstract:

Previous studies have demonstrated that vestibular compensation, the process 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 nucleus complex (VNC). The aim of the present study was to investigate the possible causal relationship between protein kinase activity and the induction of the vestibular compensation process, by delivering inhibitors of protein kinase C (PKC) or Ca(2+)/calmodulin-dependent kinase II (CaMKII) into the ipsilateral VNC at the time of the UVD and determining their effects on three 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-pyrr ole-2,5-dione, HCl (bisindolylmaleimide I, HCl/GF 109203X, HCl) ('Bis I'), at a concentration of 5 or 50 microM, significantly increased SN frequency at the earliest 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 (bisindolylmaleimide V) ('Bis V'). However, the compensation of YHT and RHT was unaffected by the PKC inhibitor. By contrast, the cell-permeable CaMKII inhibitor, myristoylated autocamtide-2 related inhibitory peptide (N-Myr-Lys-Lys-Ala-Leu-Arg-Arg-Gln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('myr-AIP') or the cell-impermeable 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 compensation of SN, YHT or RHT at any dose compared to vehicle controls. These results implicate PKC-, but not CaMKII-, signal transduction pathways in the initiation of SN compensation in guinea pig.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415238	Autocamtide-2 Related Inhibitory Peptide II, Cell-permeable			Price
IAR4244480	Protein Kinase C Inhibitor, Myristoylated			Price

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