Calcium regulation of spontaneous and asynchronous neurotransmitter release

Abstract

Summary The molecular machinery underlying action potential-evoked, synchronous neurotransmitter release, has been intensely studied. It was presumed that two other forms of exocytosis- delayed (asynchronous) and spontaneous transmission, were mediated by the same voltage-activated Ca2+ channels (VACCs), intracellular Ca2+ sensors and vesicle pools. However, a recent explosion in the study of spontaneous and asynchronous release has shown these presumptions to be incorrect. Furthermore, the finding that different forms of synaptic transmission may mediate distinct physiological functions emphasizes the importance of identifying the mechanisms by which Ca2+ regulates spontaneous and asynchronous release. In this article we will briefly summarize new and published data on the role of Ca2+ in regulating spontaneous and asynchronous release at a number of different synapses. We will discuss how an increase of extracellular [Ca2+] increases spontaneous and asynchronous release, show that VACCs are involved at only some synapses, and identify regulatory roles for other ion channels and G protein-coupled receptors. In particular, we will focus on two novel pathways that play important roles in the regulation of non-synchronous release at two exemplary synapses: one modulated by the Ca2+-sensing receptor and the other by transient receptor potential cation channel sub-family V member 1.

Calcium‐sensing receptor (CaSR) as a novel target for ischemic neuroprotection

“…In cultured neurons, activation of CaSR stimulates different types of ion channels, activates phospholipase C (PLC), and increases [Ca 2+ ] i in soma 34–37. At nerve terminals, the CaSR regulates membrane excitability38,39 and modulates neurotransmitter release 40,41. However, in vivo biological functions of these stimulatory pathways remain largely unexplored in the central nervous system (CNS).…”

Septin Dynamics Are Essential for Exocytosis

“…Spontaneous neurotransmitter release occurs in the absence of nerve stimuli, synchronous release occurs within several milliseconds after action potential generation in a presynaptic membrane, and asynchronous release persists longer after an action potential (59,60). At the molecular level, these three modes may differ in the pools of vesicles, the source of Ca 2ϩ to trigger release, and the identity of the Ca 2ϩ sensor for release but share the key SNARE-mediated fusion mechanism (59,60). This strongly suggests that septins can modulate SNARE-mediated membrane fusion.…”

Time-coded neurotransmitter release at excitatory and inhibitory synapses

“…S4 A-B1, respectively. One way is to assume that Ca 2+ channels open stochastically, which changes the resting baseline of Ca 2+ concentrations (2). Increasing the Ca 2+ concentration decreases the amplitude of the parabola Γ 2 , which changes the fusion dynamics.…”

“…Asynchronous release occurs only under certain conditions (1,2). Finally, spontaneous mini-releases occur in the absence of action potentials (2).…”

“…Synchronous release is induced by rapid calcium influx and, subsequently, calcium-mediated membrane fusion (1). Asynchronous release occurs only under certain conditions (1,2). Finally, spontaneous mini-releases occur in the absence of action potentials (2).…”