A new role for type 1 ryanodine receptor

Abstract

Type 1 ryanodine receptors (RyR1) are the second most common isoform found in neurons. We hypothesize 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 we showed (J.Neuroscience 2006, 26 -7565) that L-type channels are the sensors of membrane potential for Voltage Induced Ca2+ Release (VICaR), independently of their role as Ca2+ current carriers and that RyRs are the effectors through which Ca2+ is released into the cytosol. Here we wished to determine which RyR isoforms are responsible for VICaR. We studied Ca2+ syntillas (scintilla, L., spark in synaptic structure, a nerve terminal) in two different mutant mice with a knock-in mutation in RyR1 in physiological extracellular [Ca2+]. In the first, R163C, which has a gain of function phenotype, described as leaky and causes Central Core Disease and Malignant Hyperthermia in humans, depolarization to -60mV from -80mV caused a global increase in [Ca2+]. This increase was not seen in WT where such depolarization caused only an increase in syntilla frequency. In the second RyR1 mutant, I4898T, which has a loss of function phenotype, described as EC uncoupling, and causes Central Core Disease in humans, there was not only an absence of the global increase in [Ca2+] but also a significant decrease in syntilla frequency at −60mV compared to −80mV. Moreover basal [Ca2+] in the terminals, measured using fura-2, was significantly lower in I4898T. Finally, depolarization to 0mV resulted in a 4 fold decrease in the Ca2+ transient compared to WT. These data shows, for the first time in a preparation other than skeletal muscle, that RyR1 is involved in determining global [Ca2+] both at rest and by a process of VICaR, upon depolarization.