Inhibition of Ca2* channels

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

A1 adenosine receptors are inhibitory in the central nervous system. A receptors were originally characterized on the basis of their ability to inhibit adenylyl cyclase in adipose tissue. A number of other G-protein-mediated effectors of A receptors have subsequently been discovered these include activation of K+ channels, extensively characterized in striatal neurons [13], and inhibition of Ca2+ channels, extensively characterized in dorsal root ganglion cells [14]. Activation of A receptors has been shown to produce a species-dependent stimulation or inhibition of the phosphatidylinositol pathway in cerebral cortex. In other tissues, activation of A receptors results in synergistic activation of the phosphatidylinositol pathway in concert with Ca2+-mobilizing hormones or neurotransmitters [15]. The effectors of A adenosine receptors and other purinergic receptor subtypes are summarized in Table 17-2. 

Opioid receptors generally mediate neuronal inhibition. They couple to G or G0> and produce inhibition of Ca2+ channels and opening of K+ channels. They also inhibit adenylyl cyclase. Through this and other downstream signaling pathways, opioid receptors modulate... 

Swartz, K. J., Merritt, A., Bean, B. P., and Lovinger, D. M. (1993) Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission. Nature 361,165-168. 

As a result of these actions opioids inhibit neurotransmission at the presynaptic and postsynaptic sites. Presynaptic inhibition depends mostly on the direct inhibitory effect on transmitter exocytosis from membrane-associated storage vessels. This direct effect is increased by the inhibition of Ca2+ channels, since Ca2+ ions trigger the transmitter release. Activation of K+ ions induces membrane hyperpolarization which is the most important action component of postsynaptic inhibition. 

Garcia DE, Li B, Garcia-Ferreiro RE, Hernandez-Ochoa EO, Yan K, Gautam N, Catterall WA, Mackie K, Hille B (1998) G-protein beta-subunit specificity in the fast membrane-delimited inhibition of Ca2+ channels. J Neurosci 18 9163-70 Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271 5768-76... 

Sutton KG, McRory JE, Guthrie H, Murphy TH, Snutch TP (1999) P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-lA. Nature 401 800-4 Swartz KJ (1993) Modulation of Ca2+ channels by protein kinase C in rat central and peripheral neurons disruption of G protein-mediated inhibition. Neuron 11 305-20 Swartz KJ, Merritt A, Bean BP, Lovinger DM (1993) Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission. Nature 361 165-8 Takahashi SX, Miriyala J, Colecraft HM (2004) Membrane-associated guanylate kinase-like properties of beta-subunits required for modulation of voltage-dependent Ca2+ channels. Proc Natl Acad Sd US A 101 7193-8... 

Fig. 4 Two mechanisms for G-protein inhibition of Ca2+ channels, (a) GPy subunits from activated G0a(Sybind to channel and displace channel fi-subunit, thereby reducing channel sensitivity to membrane depolarization, (b) Activated Gaq activates phospholipase C (PLC) so hydrolyzing membrane phosphatidylinositol-4,5-bisphosphate (PIP2), normally required to stabilize the channel open state.

Delmas P, Abogadie FC, Milligan G et al (1999) betagamma dimers derived from Go and Gi proteins contribute different components of adrenergic inhibition of Ca2+ channels in rat sympathetic neurones. J Physiol 518 23-36... 

In the calyx of Held synapse in the auditory brainstem of rats the 5-HTib receptor inhibition of glutamate release was fully explained by inhibition of Ca2+ entry through voltage-dependent channels (Mizutani et al. 2006). In rat nucleus accumbens, in contrast, the analogous 5-HTib effect did not involve inhibition of Ca2+ channels (Muramatsu et al. 1998). In rat amygdala, the 5-HTia inhibition operated via a cyclic AMP pathway and apparently inhibition of Ca2+ entry an unexplained observation was the failure of pertussis toxin to abolish the 5-HTia inhibition (Cheng et al. 1998). 

On the other hand, a2-adrenoreceptors mostly mediate their intracellular signalling through G,. In this case, the signalling through the Ga and Gpy subunits may be important. Activation of the Gm leads to the inhibition of adenylyl cyclase (AC) with a reduction in cAMP levels, whereas activation of Gpy leads to inhibition of Ca2+ channels and activation of K+ channels and mitogen-activated protein kinases MAPK (Hein et al., 2006). 

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