Open AccessLeucine‐rich repeat kinase 2 ( LRRK 2) inhibitors differentially modulate glutamate release and Serine935 LRRK 2 phosphorylation in striatal and cerebrocortical synaptosomes
Author(s) -
Mercatelli Daniela,
Bolognesi Paolo,
Frassineti Martina,
Pisanò Clarissa A.,
Longo Francesco,
Shimshek Derya R.,
Morari Michele
Publication year - 2019
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.484
Subject(s) - lrrk2 , dopaminergic , glutamate receptor , dopamine , kinase , biology , neurotransmitter , pharmacology , striatum , microbiology and biotechnology , chemistry , neuroscience , biochemistry , receptor , mutation , central nervous system , gene
Mutations in leucine‐rich repeat kinase 2 ( LRRK 2 ) gene have been pathogenically linked to Parkinson's disease, and pharmacological inhibition of LRRK 2 is being pursued to tackle nigro‐striatal dopaminergic neurodegeneration. However, LRRK 2 kinase inhibitors may have manifold actions, affecting not only pathological mechanisms in dopaminergic neurons but also physiological functions in nondopaminergic neurons. Therefore, we investigated whether LRRK 2 kinase inhibitors differentially modulate dopamine and glutamate release from the mouse striatum and cerebral cortex. Spontaneous and KC l‐evoked [ 3 H]‐dopamine and glutamate release from superfused synaptosomes obtained from wild‐type and LRRK 2 knock‐out, kinase‐dead or G2019S knock‐in mice was measured. Two structurally unrelated inhibitors, LRRK 2‐ IN ‐1 and GSK 2578215A, were tested. LRRK 2, phosphoSerine1292 and phosphoSerine935 LRRK 2 levels were measured in all genotypes, and target engagement was evaluated by monitoring phosphoSerine935 LRRK 2. LRRK 2‐ IN ‐1 inhibited striatal glutamate but not dopamine release; GSK 2578215A inhibited striatal dopamine and cortical glutamate but enhanced striatal glutamate release. LRRK 2‐ IN ‐1 reduced striatal and cortical phosphoSerine935 levels whereas GSK 2578215A inhibited only the former. Neither LRRK 2 inhibitor affected neurotransmitter release in LRRK 2 knock‐out and kinase‐dead mice; however, they facilitated dopamine without affecting striatal glutamate in G2019S knock‐in mice. GSK 2578215A inhibited cortical glutamate release in G2019S knock‐in mice. We conclude that LRRK 2‐ IN ‐1 and GSK 2578215A modulate exocytosis by blocking LRRK 2 kinase activity, although their effects vary depending on the nerve terminal examined. The G2019S mutation unravels a dopamine‐promoting action of LRRK 2 inhibitors while blunting their effects on glutamate release, which highlights their positive potential for the treatment of PD , especially of LRRK 2 mutation carriers.