PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting
| Autor: | Selwyn S. Jayakar, Samantha Cole, Eric R. Starr, Zack Dale, Joseph F. Margiotta, Phyllis C. Pugh |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
endocrine system
A Kinase Anchor Proteins Chick Embryo Nitric Oxide Synthase Type I Receptors Nicotinic Biology Neurotransmission Autonomic Nervous System Nitric Oxide Synapse 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Postsynaptic potential medicine Animals Protein kinase A Molecular Biology Cells Cultured 030304 developmental biology Neurons 0303 health sciences Neuronal Plasticity Ciliary ganglion Cell Biology Cyclic AMP-Dependent Protein Kinases Nicotinic acetylcholine receptor Synapses Synaptic plasticity Pituitary Adenylate Cyclase-Activating Polypeptide Calcium Neuroscience hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Acetylcholine Protein Binding medicine.drug |
| Zdroj: | Molecular and Cellular Neuroscience. 63:1-12 |
| ISSN: | 1044-7431 |
| DOI: | 10.1016/j.mcn.2014.08.007 |
| Popis: | Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of α7 subunits (α7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with α7-nAChRs, many of which are perisynaptic, as well as with heteromeric α3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such coordination has broad relevance for understanding the control of autonomic synapses and consequent visceral functions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect