Functional Coupling of Ca2+ Channels to Ryanodine Receptors at Presynaptic Terminals

Abstract

Ca2+-induced Ca2+ release (CICR) enhances a variety of cellular Ca2+ signaling and functions. How CICR affects impulse-evoked transmitter release is unknown. At frog motor nerve terminals, repetitive Ca2+ entries slowly prime and subsequently activate the mechanism of CICR via ryanodine receptors and asynchronous exocytosis of transmitters. Further Ca2+ entry inactivates the CICR mechanism and the absence of Ca2+ entry for >1 min results in its slow depriming. We now report here that the activation of this unique CICR markedly enhances impulse-evoked exocytosis of transmitter. The conditioning nerve stimulation (10–20 Hz, 2–10 min) that primes the CICR mechanism produced the marked enhancement of the amplitude and quantal content of end-plate potentials (EPPs) that decayed double exponentially with time constants of 1.85 and 10 min. The enhancement was blocked by inhibitors of ryanodine receptors and was accompanied by a slight prolongation of the peak times of EPP and the end-plate currents estimated from deconvolution of EPP. The conditioning nerve stimulation also enhanced single impulse- and tetanus-induced rises in intracellular Ca2+ in the terminals with little change in time course. There was no change in the rate of growth of the amplitudes of EPPs in a short train after the conditioning stimulation. On the other hand, the augmentation and potentiation of EPP were enhanced, and then decreased in parallel with changes in intraterminal Ca2+ during repetition of tetani. The results suggest that ryanodine receptors exist close to voltage-gated Ca2+ channels in the presynaptic terminals and amplify the impulse-evoked exocytosis and its plasticity via CICR after Ca2+-dependent priming.

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

“…First, inositoltrisphosphate (InsP 3 ) receptors are immunolocalized in presynaptic terminals of the deep cerebellar nuclei and retina 7,8 . Second, at the frog neuromuscular junction, agents that affect ryanodine-sensitive Ca 2+ stores also regulate presynaptic intracellular Ca 2+ (Ca 2+ i ) rises and acetylcholine release during high-frequency stimulation 9,10 . Third, action-potential-evoked release of acetylcholine at synapses in Aplysia buccal ganglia is inhibited by ryanodine and augmented by presynaptic injection of cyclic ADP ribose 11 .…”

Calcium release via activation of presynaptic IP3 receptors contributes to kainate-induced IPSC facilitation in rat neocortex

“…Presynaptic activation of CICR is known to regulate neurotransmitter release (Narita et al, 1998(Narita et al, , 2000 and has been implicated in some but not all (Breustedt and Schmitz 2004) studies of KAR induced facilitation. We demonstrate the presence of functional presynaptic KARs in the prefrontal cortex that are involved in the modulation of GABAergic transmission.…”

Presynaptic Ryanodine Receptors Are Required for Normal Quantal Size at theCaenorhabditis elegansNeuromuscular Junction

“…However, emerging evidence suggests that ryanodine receptor (RYR)-mediated Ca 2ϩ release from the endoplasmic reticulum (ER) may also play a role in synaptic exocytosis. Blockade of RYRs with ryanodine in vertebrate brain slices or other preparations inhibits the frequency and amplitude of miniature postsynaptic currents (mPSCs) (Llano et al, 2000;Sharma and Vijayaraghavan, 2003), the amplitude of evoked postsynaptic currents (ePSCs) (Narita et al, 2000;Galante and Marty, 2003), paired pulse facilitation (Emptage et al, 2001), and presynaptic Ca 2ϩ transients (Llano et al, 2000;Narita et al, 2000;Emptage et al, 2001;De Crescenzo et al, 2004).…”

“…However, ryanodine may either activate or block RYRs depending on its concentration (Xu et al, 1998;Llano et al, 2000;Narita et al, 2000). The lack of a clear boundary between concentrations required for the two different actions may have contributed to the controversy.…”