Crosstalk between G proteins and protein kinase C mediated by the calcium channel α1 subunit

Abstract

The modulation of voltage-dependent Ca2+ channels at presynaptic nerve terminals is an important factor in the control of neurotransmitter release and synaptic efficacy. Some terminals contain multiple Ca2(+)-channel subtypes (N and P/Q), which are differentially regulated by G-protein activation and by protein kinase C (PKC)-dependent phosphorylation. Regulation of channel activity by crosstalk between second messenger pathways has been reported although the molecular mechanisms underlying crosstalk have not been described. Here we show that crosstalk occurs at the level of the presynaptic Ca2(+)-channel complex. The alpha1 subunit domain I-II linker, which connects the first and second transmembrane domains, contributes to the PKC-dependent upregulation of channel activity, while G-protein-dependent inhibition occurs through binding of Gbetagamma to two sites in the I-II linker. Crosstalk results from the PKC-dependent phosphorylation of one of the Gbetagamma binding sites which antagonizes Gbetagamma-induced inhibition. The results provide a mechanism for the highly regulated and dynamic control of neurotransmitter release that depends on the integration of multiple presynaptic signals.

The cytoplasmic coiled-coil mediates cooperative gating temperature sensitivity in the voltage-gated H+ channel Hv1

“…Findings derived from the study of Hv channels, a minimal voltage-gated channel, may offer principles common to other larger and more complex ion channels; force transmission between the cytoplasmic domain and the gate within the transmembrane region may also occur in other ion channels in which gating modulators interact with a region adjacent to the transmembrane gate [39][40][41][42][43] .…”

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

“…In the case of the μ-opioid receptor, agonist binding causes activation of G proteins, primarily of the G o subtype (Moises et al, 1994;Jiang et al, 1998). The βγ subunits of the G protein heterotrimer dissociate from the α subunit and mediate inhibition of VGCC by direct binding to the α subunit of the VGCC (Herlitze et al, 1996;Ikeda, 1996;Zamponi et al, 1997;Delmas et al, 1998;Zamponi and Snutch, 1998). Because the GABA B receptor has also been shown to inhibit VGCC by activating G o (Menon-Johansson et al, 1993;Kajikawa et al, 2001), the lack of effect of NGF on baclofen-mediated inhibition of I Ba in the present study indicates that NGF did not alter the function of G protein subunits or their coupling to VGCC.…”

“…One of these effects, mediated directly by G protein subunit interactions, is a modulation of VGCC in sensory neurons which leads to marked decreases in currents through VGCC. Opioid-mediated inhibition of VGCC is regulated by several kinases, including protein kinase C and PLC (Swartz, 1993;Zhu and Ikeda, 1994;Zamponi et al, 1997;Zhu and Yakel, 1997;King et al, 1999;Xie et al, 1999;Barrett and Rittenhouse, 2000). In addition, PI3 kinase and MAP kinases may be involved in opioid receptor desensitization (Schmidt et al, 2000;Tan et al, 2003).…”

cGMP/Protein Kinase G-Dependent Inhibition of N-Type Ca2+Channels Induced by Nitric Oxide in Human Neuroblastoma IMR32 Cells

“…Evidence has been accumulating that neurotransmitters induce voltage-dependent as well as voltage-independent modulation of calcium channels (Marchetti et al, 1986; for review, see Tsien et al, 1988;Carbone and Swandulla, 1989;Dolphin, 1995Dolphin, , 1998Zamponi et al, 1997;Dunlap and Ikeda, 1998). G-protein-mediated inhibition of these channels is characterized by a slowing of the current activation kinetics, which has been attributed to a time-dependent recovery from voltage-dependent inhibition (Bean, 1989).…”