title: Presynaptic inhibition by α2 receptor/adenylate cyclase/PDE4 complex at retinal rod bipolar synapse.
abstract: G-protein-coupled receptor (GPCR)-mediated presynaptic inhibition is a fundamental mechanism regulating synaptic transmission in the CNS. The classical GPCR-mediated presynaptic inhibition in the CNS is produced by direct interactions between the G(βγ) subunits of the G-protein and presynaptic Ca(2+) channels, K(+) channels, or synaptic proteins that affect transmitter release. This mode of action is shared by well known GPCRs such as the α2, GABA(B), and CB1 receptors. We report that the α2 receptor-mediated inhibition of presynaptic Ca(2+) channel and transmitter release in rat retinal rod bipolar cells depends on the G(α) subunit via a G(α)-adenylate cyclase-cAMP cascade and requires participation of the type 4 phosphodiesterase (PDE4), a new role for phosphodiesterase in neural signaling. By using the G(α) instead of the G(βγ) subunits, this mechanism is able to use a cyclase/PDE enzyme pair to dynamically control a cyclic nucleotide second messenger (i.e., cAMP) for the regulation of synaptic transmission, an operating strategy that shows remarkable similarity to that of dynamic control of cGMP and transmitter release from photoreceptors by the guanylate cyclase/PDE6 pair in phototransduction. Our results demonstrate a new paradigm of GPCR-mediated presynaptic inhibition in the CNS and add a new regulatory mechanism at a critical presynaptic site in the visual pathway that controls the transmission of scotopic information. They also provide a presynaptic mechanism that could contribute to neuroprotection of retinal ganglion cells by α2 agonists, such as brimonidine, in animal models of glaucoma and retinal ischemia and in glaucoma patients.
authors.affiliation: Vision Sparing Team, Department of Biological Sciences, Allergan Inc., Irvine, California 92612 dong_james@allergan.com.
authors.forename: Cun-Jian
authors.initials: CJ
authors.lastname: Dong
authors.affiliation: Vision Sparing Team, Department of Biological Sciences, Allergan Inc., Irvine, California 92612.
authors.forename: Yuanxing
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Vision Sparing Team, Department of Biological Sciences, Allergan Inc., Irvine, California 92612.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Vision Sparing Team, Department of Biological Sciences, Allergan Inc., Irvine, California 92612.
authors.forename: William A
authors.initials: WA
authors.lastname: Hare
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D055254:Night Vision / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000262:Adenylyl Cyclases
keywords: Ca2+ channel; GPCR; PDE4; presynaptic inhibition; α2 receptor