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Calcium‐activated K + channel K Ca 3.1 Plays a Pro‐inflammatory Role in α‐Synuclein Models of Parkinson's Disease
Author(s) -
Malovic Emir,
Sarkar Souvarish,
Nguyen Hai,
Singh Vikrant,
Jin Huajun,
Anantharam Vellareddy,
Kanthasamy Arthi,
Wulff Heike,
Kanthasamy Anumantha G.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.500.20
Subject(s) - neuroinflammation , microglia , proinflammatory cytokine , downregulation and upregulation , neurodegeneration , chemistry , voltage dependent calcium channel , calcium channel , calcium , microbiology and biotechnology , pharmacology , inflammation , medicine , biology , biochemistry , immunology , disease , gene , organic chemistry
Chronic neuroinflammation characterized by the sustained activation of microglia and subsequent release of pro‐inflammatory mediators is concomitant with the progressive neurodegeneration observed in Parkinson's disease (PD). Microglial potassium channels have a well‐developed pharmacology and constitute attractive targets for reducing neuroinflammation. We previously implicated the voltage‐gated channel K v 1.3 in playing a proinflammatory role in cell culture and animal models of PD. Another K + channel, the calcium activated channel K Ca 3.1 is also expressed in a variety of immune cells, including B cells, T cells, and microglia. However, the role of K Ca 3.1 in PD‐related neuroinflammatory processes has not been investigated. In this study, we examined whether K Ca 3.1 plays a role in regulating neuroinflammation in PD. Exposure of primary mouse microglia to aggregated α‐synuclein (α‐Syn agg ) led to the upregulation of K Ca 3.1 mRNA, as determined by qRT‐PCR. Patch‐clamp recordings revealed that K Ca 3.1 activity is also upregulated following α‐Syn agg stimulation. We further demonstrated that α‐Syn agg increases the production of pro‐inflammatory cytokines, including IL‐1β, IL‐6, IL‐12, and TNFα, while these cytokines were significantly attenuated with the K Ca 3.1 inhibitor, TRAM‐34 (1‐[(2‐chlorophenyl)diphenylmethyl]‐1H‐pyrazole). Using proteomics analysis, we identified potential targets that may be involved in K Ca 3.1 signaling in α‐Syn agg ‐treated samples. In animal studies, C57BL/6J mice received a unilateral stereotaxic injection of mouse α‐synuclein preformed fibrils (α‐Syn pff ) in the striatum. One subset of these animals received TRAM‐34 (10 mg/kg, i.p.) daily starting at 4 months and animals were sacrificed one month later. Behavioral analysis revealed α‐Syn pff ‐induced motor deficits at 5 months post‐injection, whereas TRAM‐34 attenuated α‐Syn pff ‐induced motor deficits. TRAM‐34 was also able to significantly block α‐Syn pff ‐induced decreases in striatal dopamine and DOPAC levels. This was further corroborated by TRAM‐34's protection against the α‐Syn pff ‐induced loss of tyrosine hydroxylase in both substantia nigral and striatal tissues by immunohistochemistry and immunoblotting, respectively. Collectively, our data highlight the pivotal role of K Ca 3.1 in PD‐associated neuroinflammatory processes and has potential therapeutic implications. Support or Funding Information (NIH grants NS100090, NS088206 and ES026892) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .