Fast cAMP Modulation of Neurotransmission via Neuropeptide Signals and Vesicle Loading.
Cyclic AMP (cAMP) signaling augments synaptic transmission, but because many targets of cAMP and protein kinase A (PKA) may be involved, mechanisms underlying this pathway remain unclear. To probe this mechanism, we used optogenetic stimulation of cAMP signaling by Beggiatoa-photoactivated adenylyl cyclase (bPAC) in Caenorhabditis elegans motor neurons. Behavioral, electron microscopy (EM), and electrophysiology analyses revealed cAMP effects on both the rate and on quantal size of transmitter release and led to the identification of a neuropeptidergic pathway affecting quantal size. cAMP enhanced synaptic vesicle (SV) fusion by increasing mobilization and docking/priming. cAMP further evoked dense core vesicle (DCV) release of neuropeptides, in contrast to channelrhodopsin (ChR2) stimulation. cAMP-evoked DCV release required UNC-31/Ca2+-dependent activator protein for secretion (CAPS). Thus, DCVs accumulated in unc-31 mutant synapses. bPAC-induced neuropeptide signaling acts presynaptically to enhance vAChT-dependent SV loading with acetylcholine, thus causing increased miniature postsynaptic current amplitudes (mPSCs) and significantly enlarged SVs.
Buchmann Institute for Molecular Life Sciences, Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt, Germany; Department of Biochemistry, Chemistry and Pharmacy, Institute for Biophysical Chemistry, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
Wagner
W
Steuer Costa
Buchmann Institute for Molecular Life Sciences, Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt, Germany; Department of Biochemistry, Chemistry and Pharmacy, Institute for Biophysical Chemistry, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
Szi-Chieh
SC
Yu
Buchmann Institute for Molecular Life Sciences, Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt, Germany; Department of Biochemistry, Chemistry and Pharmacy, Institute for Biophysical Chemistry, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
Jana F
JF
Liewald
Buchmann Institute for Molecular Life Sciences, Goethe University, Max-von-Laue-Strasse 15, 60438 Frankfurt, Germany; Department of Biochemistry, Chemistry and Pharmacy, Institute for Biophysical Chemistry, Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany. Electronic address: a.gottschalk@em.uni-frankfurt.de.
Alexander
A
Gottschalk
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D059329:Cholinergic Neurons / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D009046:Motor Neurons / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism
D009479:Neuropeptides; D000242:Cyclic AMP
CAPS; Caenorhabditis elegans; ChR2; PKA; bPAC; flash’n’freeze electron microscopy; neuromodulation; optogenetics; synaptic vesicle diameter; vAChT