title: Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.
abstract: Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.
authors: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Pablo J
authors: PJ
authors: Sáez
authors: Juan A
authors: JA
authors: Orellana
authors: Natalia
authors: N
authors: Vega-Riveros
authors: Vania A
authors: VA
authors: Figueroa
authors: Diego E
authors: DE
authors: Hernández
authors: Juan F
authors: JF
authors: Castro
authors: Andrés D
authors: AD
authors: Klein
authors: Jean X
authors: JX
authors: Jiang
authors: Silvana
authors: S
authors: Zanlungo
authors: Juan C
authors: JC
authors: Sáez
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D000906:Antibodies; D018031:Connexin 43; D017630:Connexins; D047908:Intracellular Signaling Peptides and Proteins; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D009419:Nerve Tissue Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C503631:Panx1 protein, mouse; D011506:Proteins; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate; D002118:Calcium
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