Presynaptic Ca2+ channels, CaV2.1 and Ca V2.2, are tightly coupled to neurotransmitter release with the amount of release being dependent on the 3rd or 4th power of Ca2+ entry. Ca2+-binding proteins like calmodulin (CaM) and the related,MorePresynaptic Ca2+ channels, CaV2.1 and Ca V2.2, are tightly coupled to neurotransmitter release with the amount of release being dependent on the 3rd or 4th power of Ca2+ entry.
Ca2+-binding proteins like calmodulin (CaM) and the related, neuron-specific neuronal Ca2+ sensor (NCS) proteins differentially regulate CaV2.1 channels in an activity-dependent manner. Thus, regulation of these channels by CaM and NCS proteins should have profound effects on short-term synaptic plasticity.-CaM and NCS proteins, which bind to the C-terminus of CaV2.1 channels, differentially regulate channel activity while having very similar structures. We show that the amino-terminal myristoyl group, a conserved feature of NCS proteins not found in CaM, is required for differential CaV2.1 regulation by two NCS proteins, Ca2+-binding protein 1 (CaBP1) and visinin-like protein-2 (VILIP-2).
Without the myristoyl group regulation of CaV2.1 channels by CaBP1 and VILIP-2 is indistinguishable from regulation by CaM.-Sequential binding of CaM to the IQ-like motif and the CaM-binding domain (CBD) in the intracellular C-terminus of CaV2.1 mediates Ca 2+-dependent facilitation (CDF) and Ca2+-dependent inactivation (CDI), respectively, in non-neuronal cells. We show that in superior cervical ganglion (SCG) neurons, CaM or NCS proteins binding to the IQ-like motif mediates CDF of CaV2.1 channels and two forms of short-term synaptic plasticity that enhance transmission, synaptic facilitation and augmentation.
In SCG neurons, CaV2.1 regulation by CaM or NCS proteins binding to the CBD results in short-term synaptic depression. Thus, CaV2.1 regulation by CaM and NCS proteins binding provides an all-purpose mechanism for short-term synaptic plasticity.-Neurotransmitter release occurs in two phases: a fast synchronous phase and a slow asynchronous phase.
CaV2.1 regulation by CaM and NCS proteins alters synchronous release to produce short-term synaptic plasticity. Asynchronous release is regulated by neuronal activity and is Ca2+ -dependent- however, the Ca2+ source for asynchronous release is unknown. We have identified an asynchronous Ca2+ current through CaV2.1 and CaV2.2 channels.
Prolonged or repetitive Ca2+ entry through CaV2.1 or Ca V2.2 channels activates a slowly decaying Ca2+ current, IAsync, which is observed upon membrane repolarization. We propose that this Ca2+-dependent current, IAsync, is the Ca2+ source for asynchronous neurotransmitter release.