Presynaptic Ca2+/calmodulin-dependent protein kinase II modulates neurotransmitter release by activating BK channels at Caenorhabditis elegans neuromuscular junction.
Although Ca2+/calmodulin-dependent protein kinase II (CaMKII) is enriched at the presynaptic nerve terminal, its role in neurotransmitter release is poorly defined. We assessed the function of presynaptic CaMKII in neurotransmitter release and tested the hypothesis that BK channel is a mediator of presynaptic CaMKII function by analyzing miniature and evoked postsynaptic currents at the Caenorhabditis elegans neuromuscular junction. Both loss-of-function (lf) and gain-of-function (gf) of unc-43, the gene encoding CaMKII, inhibited neurotransmitter release. The inhibitory effect of unc-43(gf) was reversed by mutation or blockade of the BK channel SLO-1. SLO-1 expressed in Xenopus oocytes could be activated by recombinant rat alpha-CaMKII, and this effect of CaMKII was abolished by mutating a threonine residue (T425) at a consensus CaMKII phosphorylation site in the first RCK (regulator of conductance for K+) domain of the channel. Expression of slo-1(T425A) in neurons antagonized the inhibitory effect of unc-43(gf) on neurotransmitter release as slo-1(lf) did. The inhibitory effect of unc-43(gf) was not reversed by unc-103(lf), dgk-1(lf), or eat-16(lf), which reportedly suppress behavioral phenotypes of unc-43(gf). These observations suggest that presynaptic CaMKII is a bidirectional modulator of neurotransmitter release, presumably by phosphorylating different molecular targets, and that its negative modulatory effect on the release is mainly mediated by SLO-1 activation.
Liu
Qiang
Q
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Chen
Bojun
B
Ge
Qian
Q
Wang
Zhao-Wen
ZW
D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D023421:Models, Animal; D009469:Neuromuscular Junction / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D018377:Neurotransmitter Agents; C494845:slo-1 protein, C elegans; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517679:unc-43 protein, C elegans