Sigma receptors suppress multiple aspects of microglial activation.
During brain injury, microglia become activated and migrate to areas of degenerating neurons. These microglia release proinflammatory cytokines and reactive oxygen species causing additional neuronal death. Microglia express high levels of sigma receptors, however, the function of these receptors in microglia and how they may affect the activation of these cells remain poorly understood. Using primary rat microglial cultures, it was found that sigma receptor activation suppresses the ability of microglia to rearrange their actin cytoskeleton, migrate, and release cytokines in response to the activators adenosine triphosphate (ATP), monocyte chemoattractant protein 1 (MCP-1), and lipopolysaccharide (LPS). Next, the role of sigma receptors in the regulation of calcium signaling during microglial activation was explored. Calcium fluorometry experiments in vitro show that stimulation of sigma receptors suppressed both transient and sustained intracellular calcium elevations associated with the microglial response to these activators. Further experiments showed that sigma receptors suppress microglial activation by interfering with increases in intracellular calcium. In addition, sigma receptor activation also prevented membrane ruffling in a calcium-independent manner, indicating that sigma receptors regulate the function of microglia via multiple mechanisms.
Hall
Aaron A
AA
Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida 33612-4799, USA.
Herrera
Yelenis
Y
Ajmo
Craig T
CT
Cuevas
Javier
J
Pennypacker
Keith R
KR
D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005470:Fluorometry; D015759:Ionomycin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*
D000199:Actins; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; D008070:Lipopolysaccharides; D017480:Receptors, sigma; D009569:Nitric Oxide; D015759:Ionomycin; D000255:Adenosine Triphosphate; D002118:Calcium