IP₃R – regulator of RyR or safety valve?
Although it is known that IP₃R is also found in the membrane of the sarcoplasmic reticulum, its localisation in relation to the RyR clusters remains undetermined. The localisation and functional interaction with RyR are crucial for the significance of abnormal IP₃R function in the ankyrin-B syndrome and heart failure.
We have formulated two hypotheses regarding the role of IP₃R (Fig. 1a, Fig. 1b): If IP₃R is co-localised with RyR, it is possible that it plays a part as regulator of the Ca2+-induced Ca2+ release. Ca2+ release from IP₃R can change the local Ca2+ concentration around RyR and thereby influence RyR’s sensitivity to Ca2+ (Fig. 1b). This would be an example illustrating that an interaction between different proteins in the same microdomain in the heart muscle cells can result in more precise regulation of the contraction.
Alternatively, IP₃R may play a part as a «safety valve» in the sarcoplasmic reticulum (Fig. 1a): Localisation of IP₃R in the same microdomain as NKA and NCX means that Ca2+ released through IP₃R can be easily transported out of the cell in a controlled manner. It is well known that accumulation of Ca2+ in the heart muscle cells has a positive effect in the form of increased inotropy. But if the accumulation becomes too large, Ca2+ will «leak» in an uncontrolled manner from the sarcoplasmic reticulum through RyR. As previously described, such RyR leakage could activate NCX, lead to afterdepolarisations and trigger arrhythmias. In recent years, however, it has been found that leakage from the sarcoplasmic reticulum may also take place «silently», independently of RyR (25). It is conceivable that such leakage could take place through IP₃R. It is therefore very interesting that heart failure, the end-point of many heart diseases, is associated with an increased amount of IP₃R in the heart (22, 26).
Heart failure is also associated with increased activity in the sympathetic nervous system and in the endothelin and renin-angiotensin systems. Since this means increased production of IP₃, IP₃R and its microdomain may play a larger part in heart failure than in healthy hearts (22). At present it is not known whether this is a protective mechanism to prevent over-filling of the sarcoplasmic reticulum, whether it contributes to weakened contractility by reducing the Ca2+ reservoir, or whether it increases the risk of arrhythmias by making RyR «hypersensitive». Clearly, both this and other microdomains in heart muscle cells should be studied further to enable an understanding of how the heart functions under normal circumstances and during illness.