Protein kinase A and calcium/calmodulin-dependent protein kinase II regulate D-[3H]aspartate release in auditory brain stem nuclei.

Abstract

We noted previously that after unilateral cochlear ablation (UCA) in young adult guinea pigs, plastic changes in glutamatergic transmitter release in several brain stem auditory nuclei depended on protein kinase C. In this study, we assessed whether such changes depended on protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII). The electrically-evoked release of D-[3H]aspartate (D-[3H]Asp) was quantified in vitro as an index of glutamatergic transmitter release in the major subdivisions of the cochlear nucleus (CN) and the main nuclei of the superior olivary complex (SOC). In tissues from intact animals, dibutyryl-cyclic adenosine monophosphate (DBcAMP), a PKA activator, elevated D-[3H]Asp release by 1.9-3.7-fold. The PKA inhibitor, H-89 (2 microM), did not alter the evoked release but blocked the stimulatory effects of DBcAMP. These findings suggested that PKA could positively regulate glutamatergic transmitter release. Seven days after the ablation of one cochlea and its cochlear nerve, the stimulatory effect of DBcAMP remained evident. After 145 postablation days, H-89 blocked the plastic elevations of D-[3H]Asp release in the ipsilateral CN and lateral (LSO) and medial (MSO) superior olive. A CaMKII inhibitor, KN-93, produced similar blocks, suggesting that the postablation plasticities in these nuclei depended on PKA or CaMKII. Both H-89 and KN-93 elevated release in the medial nucleus of the trapezoid body (MNTB) and the contralateral MSO, suggesting that either kinase could be used by endogenous mechanisms in these nuclei to downregulate glutamatergic release.