Somatostatin-induced inhibition of neuronal Ca2+ current modulated by cGMP-dependent protein kinase

Abstract

Neurotransmitter release is frequently regulated by peptides that modulate neuronal calcium channels. Whole-cell recordings show that the ion permeability and voltage dependence of these channels are controlled by a membrane-associated pathway involving GTP-binding proteins. Here we use perforated-patch recordings to show that, in addition to this pathway, the peptide somatostatin inhibits the calcium current in chick ciliary ganglion neurons by a second soluble pathway involving a cyclic GMP-dependent protein kinase (cGMP-PK). This somatostatin inhibition of Ca2+ current did not desensitize and was not characterized by the slowing of Ca(2+)-current activation (kinetic slowing) observed in whole-cell recordings. When cGMP-PK was inhibited, somatostatin inhibition of Ca2+ current resembled that observed with whole-cell recordings. cGMP agonists mimic the effect of somatostatin only in perforated patch recordings. An endogenous cGMP-PK therefore forms part of the mechanism by which somatostatin induces a sustained inhibition of neuronal calcium channels.

A Nitric Oxide/Cyclic GMP‐Dependent Protein Kinase Pathway Alters Transmitter Release and Inhibition by Somatostatin at a Site Downstream of Calcium Entry

“…These studies led to the hypothesis that somatostatin-mediated G protein activation causes a decrease in presynaptic Ca2+ current resulting in decreased ACh release. Electrophysiological recordings from the soma of these neurons in culture confirmed that somatostatin strongly inhibited Ca2+ current in a pertussis toxinsensitive manner (Dryer et al, 1991;Meriney et al, 1994). Furthermore, one of these previous reports implicated a cytoplasmic cyclic GMP (cGMP)-dependent protein kinase (PKG) pathway that altered the characteristics of the membrane-delimited somatostatin-mediated inhibition of Ca2+ current (Meriney et al, 1994).…”

“…Electrophysiological recordings from the soma of these neurons in culture confirmed that somatostatin strongly inhibited Ca2+ current in a pertussis toxinsensitive manner (Dryer et al, 1991;Meriney et al, 1994). Furthermore, one of these previous reports implicated a cytoplasmic cyclic GMP (cGMP)-dependent protein kinase (PKG) pathway that altered the characteristics of the membrane-delimited somatostatin-mediated inhibition of Ca2+ current (Meriney et al, 1994). In this report, we demonstrate that the PKG pathway interacts with the somatostatin-mediated modulation of ACh release from ciliary ganglion neurons and hypothesize that this occurs at a site after Ca2+ entry.…”

Novel signals mediating the functions of somatostatin: The emerging role of NO/cGMP

“…As in other systems, it activates a soluble GC (Koch et al, 1994;Ding and Weinberg, 2007) leading to an increase in cGMP production. cGMP is an important regulator of retinal physiology, since it influences a series of biochemical substrates including ion channels (Meriney et al, 1994). It modulates gap…”

“…A c c e p t e d M a n u s c r i p t 17 cGMP-dependent protein kinase (Meriney et al,1994). cGMP was shown to be important in somatostatin's protective actions against NMDA induced neuronal death in cortical cultures (Forloni et al, 1997).…”

“…In addition, activation of the receptors leads to the regulation of ion channels, affecting potassium and calcium currents (Meriney et al, 1994;Tallent et al, 1996;Akopian et al, 2000).…”