Chlorocresol: an activator of ryanodine receptor-mediated Ca2+ release.
In the present study we investigated the effect of the compound chlorocresol on intracellular Ca2+ homeostasis. Three different systems that have been shown to express the ryanodine receptor Ca2+ channel were chosen, i.e., skeletal muscle sarcoplasmic reticulum, cerebellar microsomes, and PC12 cells. In skeletal muscle sarcoplasmic reticulum, 4-chloro-m-cresol was found to be a potent activator of Ca2+ release mediated by a ruthenium red/caffeine-sensitive Ca2+ release channel. In cerebellar microsomes, this compound released Ca2+ from an inositol-1,4,5-trisphosphate-insensitive store, suggesting that there too it was acting at the ryanodine receptor level. When tested on PC12 cells, chlorocresol released Ca2+ from a caffeine- and thapsigargin-sensitive intracellular store. In addition, the compound was capable of releasing Ca2+ after pretreatment of PC12 cells with bradykinin, suggesting that it acts on a channel contained within an intracellular Ca2+ store that is distinct from that sensitive to inositol-1,4,5-trisphosphate. Structure-activity relationship analyses suggest that the chloro and methyl groups in chlorocresols are important for the activation of the ryanodine receptor Ca2+ release channel.
Zorzato
F
F
Institute of General Pathology, University of Ferrara, Italy.
Scutari
E
E
Tegazzin
V
V
Clementi
E
E
Treves
S
S
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003408:Cresols / Q000737:chemistry / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D015220:Calcium Channels; D003408:Cresols; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D002118:Calcium