Abstract
Ca(2+)-induced Ca(2+) release (CICR) is a ubiquitous mechanism by which Ca(2+) release from the endoplasmic reticulum amplifies the trigger Ca(2+) entry and generates propagating Ca(2+) waves. To elucidate the mechanisms that control this positive feedback, we investigated the spatial and temporal kinetics and measured the gain function of CICR in small sensory neurons from mammalian dorsal root ganglions (DRGs). We found that subsurface Ca(2+) release units (CRUs) are under tight local control by Ca(2+) entry, whereas medullar CRUs as a "common pool" system are recruited by inwardly propagating CICR. Active CRUs often displayed repetitive Ca(2+) sparks, conferring the ability to encode a "memory" of neuronal activity well beyond the duration of an action potential. Store Ca(2+) reserve was able to support all CRUs each to fire approximately 15 sparks, excluding use-dependent inactivation or store depletion as the major CICR termination mechanism. Importantly, CICR in DRG neurons operated in a low gain, linear regime (gain = 0.54), which conferred intrinsic stability to CICR. Combined with high Ca(2+) current density (-156 pA/pF at -10 mV), such a low gain CICR system generated large intracellular Ca(2+) transients without jeopardizing the stability. These findings provide the first demonstration that CICR operating in a low gain regime can be harnessed to provide a robust and graded amplification of Ca(2+) signal in the absence of counteracting inhibitory mechanism.
Highlights
From the ‡Institute of Molecualr Medicine & National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Science, Peking University, Beijing 100871, China and the §Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224
We found that subsurface Ca2؉ release units (CRUs) are under tight local control by Ca2؉ entry, whereas medullar CRUs as a “common pool” system are recruited by inwardly propagating Ca2؉-induced Ca2؉ release (CICR)
Organization and Operation of Subsurface CRUs—Fig. 1A shows typical immunofluorescent staining of RyR3 in a small sensory neuron from rat dorsal root ganglions (DRGs), illustrating that intensely stained spots were enriched along a ring right beneath the surface membrane
Summary
Combined with high Ca2؉ current density (؊156 pA/pF at ؊10 mV), such a low gain CICR system generated large intracellular Ca2؉ transients without jeopardizing the stability. These findings provide the first demonstration that CICR operating in a low gain regime can be harnessed to provide a robust and graded amplification of Ca2؉ signal in the absence of counteracting inhibitory mechanism. We demonstrated that CICR in DRG neurons operates in the low gain, linear amplification regime in conjunction with high ICa density, which confers intrinsic stability and large Ca2ϩ transient amplitude in the absence of counteracting termination mechanisms. Our results were compared and contrasted with those from heart muscle cells, a well characterized model system of CICR
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