Ryanodine activator

Despite the recent efforts of Beroza (3), the insecticidal alkaloids of the thunder-god vine (Tripterygium ivilfordii) remain only partially characterized. A structure has been proposed for anhydrory-anodine (VIII), a major degradation product of the active principle (ryanodine) of the commercial insecticide ryania (34), and a structure for the parent compound will be proposed soon by Rapoport and his coworkers (27). This again illustrates the importance of collaboration between physical and biological scientists and the intriguing research which each can reveal to the other. 

Local and transient Ca2+ increases that propagate throughout the cytosol of individual cells in the form of waves. Ca2+ waves are generated by a positive feedback activation of Ca2+ release from the intracellular Ca2+ stores through ryanodine receptors or inositol IP3 receptors. 

Ryanodine leads to contracture of mammalian skeletal muscle, whereas it causes negative inotropism in cardiac muscle. This apparent opposite effects are due to difference in the Ca2+ extruding activity the released Ca2+ remains within cytoplasm in skeletal muscle because of low Ca2+ extruding activity, whereas the increased cytoplasmic Ca2+ is rapidly excluded out of the cytoplasm in cardiac muscle via Na+ -Ca2+ -exchange. 

The first molecule, the Ca2+ channel, is required for coupling at the triad. Skeletal muscle contains higher concentrations of this L-type Ca2+ channel that can be accounted for on the basis of measured voltage-dependent Ca2+ influx because much of the Ca2+ channel protein in the T-tubular membrane does not actively gate calcium ion movement but, rather, acts as a voltage transducer that links depolarization of the T-tubular membrane to Ca2+ release through a receptor protein in the SR membrane. The ryanodine receptor mediates sarcoplasmic reticulum Ca2+ release. The bar-like structures that connect the terminal elements of the SR with the T-tubular membrane in the triad are formed by a large protein that is the principal pathway for Ca2+ release from the SR. This protein, which binds the... 

Nelson We have done similar experiments with ryanodine on urinary bladder smooth muscle. We observe a small increase in contraction frequency in response to ryanodine. We have done experiments in which we first blocked either Ca2+-activated K+ (BK) channels or small-conductance Ca2+-activated K+ (SK) channels, and then added ryanodine. This led to an enormous increase in contractility. I am proposing that the effects of CPA would be larger if BK or SK channels were first inhibited. 

Hellstrand With regard to the question of what ryanodine is doing, if you put it onto a muscle it eliminates most SR Ca2+ release, because it opens up the SR Ca2+ channels and there is some level of communication between the stores. If you put ryanodine there you essentially kill InsP3-induced responses as well. In organ culture we have found that if you culture in the presence of ryanodine for a couple of days, the InsP3-induced release reappears, whereas there is still no ryanodine-induced release, and Ca2+ waves occur (Dreja et al 2001). We know that mitochondrial activity affects the properties of Ca2+ waves, so there is a Ca2+-dependent modulation of SR release on this level which thus presumably involves InsP3 receptors and not RyRs. It is very hard to distinguish these two receptor populations in the way they interact on the SR. 

Li PL, Tang WX, Valdivia HH, Zou AP, Campbell WB 2001 cADP-ribose activates reconstitutes ryanodine receptors from coronary arterial smooth muscle. Am J Physiol... 

McCarron The difficulty with using agonists to generate InsP3 is the additional second messengers that they produce. It is plausible that the carbachol could suppress ryanodine receptor function by activating protein kinase C. You would block the response to caffeine without gaining any information about the interaction of the two receptors on stores. 

Wayman CP, Gibson A, McFadzean I 1998 Depletion of either ryanodine- or IP3-sensitive calcium stores activates capacitative calcium entry in mouse anococcygeus smooth muscle cells. Pfliiger s Arch 435 231—239... 

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