MKP3 eliminates depolarization-dependent neurotransmitter release through downregulation of L-type calcium channel Cav1.2 expression.

Release of neurotransmitters is a fundamental and regulated process that is essential for normal brain functioning. Regulation of this process is potentially important for any neuronal process, and disruption of the release process may contribute to the pathophysiology associated with psychiatric diseases. In this work it is shown that expression of the negative regulator of mitogen-activated protein kinase (MAPK) signaling the MAPK phosphatase MKP3/DUSP6 eliminates depolarization-dependent release of dopamine in rat PC12 cells. Pharmacologic interventions with latrotroxin (LTX) or A23187, which make the cells permeable to calcium, reestablish the dopamine release. Calcium imaging also reveals that calcium influx is impaired in MKP3-expressing cells. Because acute pharmacologic inhibition of MAPKs has no effect on dopamine release in naïve PC12 cells, the MKP3-mediated elimination of neurotransmitter release must be caused by a long-term process, such as changes in gene expression. In support of this the expression of the L-type calcium channel cav1.2 alpha subunit (Cacna1c) is decreased in MKP3-expressing PC12 cells. With the reintroduction of cav1.2 expression, neurotransmitter release is restored in the MKP3-expressing PC12 cells. Thus, MKP3 expression reduces neurotransmitter release by decreasing the expression of cav1.2. Because MKP3 is increased when neuronal activity is elevated, this process could play a role in regulating neurotransmitter homeostasis.