Does Central Core Disease have a Neuronal Component?

Abstract

Type 1 ryanodine receptors (RyR1) are the second most common isoform found in neurons after RyR2. We have provided evidence that in nerve terminals from neurohypophysis, L-type Ca2+ channels are coupled to RyR1 in the same way found in EC coupling in skeletal muscle. In these nerve terminals (J.Neuroscience 2006, 26 −7565) L-type channels are the sensors of membrane potential for Voltage Induced Ca2+ Release (VICaR), independently of their role as Ca2+ current carriers, and RyRs of uknown type are the effectors through which Ca2+ is released into the cytosol. Here we wished to study whether RyRs of type 1 are mediators of VICaR in these nerve terminals. We employed a RyR1 mutant mouse (I4895T) with a loss of function phenotype that causes Central Core Disease in humans. We studied both, global [Ca2+] with Fura-2 and focal [Ca2+] in the form of Ca2+ syntillas with fluo3. When the nerve terminals were depolarized to 0mV, the mutant showed a 4-fold decrease in the global Ca2+ transient compared to WT. This very large decrease in the Ca2+ transient occurred in the absence of any change in the Ca2+ current. In the absence of external Ca2+, we also demonstrated the presence of VICaR in WT. Moreover, in the WT depolarization to 0mV from −80mV induced a 3 fold increase in syntilla frequency due to VICaR (i.e. in the absence of external Ca2+). VICaR was totally absent in the mutant. These data show for the first time the involvement of type 1 RyRs during depolarization of nerve terminals. This suggests that Central Core Disease has a neuronal component as well as a skeletal muscle component.( Supported by grants from NIH GM087580-01 to JW and AHA 0835580D to VD.)