Ca2‘-channel activator

BAYK8644 is a DHP with Ca2+ channel activating properties. Although some therapeutic effects can be envisaged for such drugs (such as stimulation of glucose-dependent insulin secretion, positive inotropy), severe side effects are also predicted from animal studies (dystonic neurobehavioral syndrome, hypertension, arrhythmias), which currently prevents their clinical development. 

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... 

Further support for a link between voltage-dependent Ca2+ channel activity and KCa channel activity was the present observation that during a depolarization (after 200 ms) the time course of change in the open probability of Kca channels was similar to that of Ica as it inactivated. Since KCa channels themselves do not exhibit voltage-dependent inactivation at OmV, the reduction in the open probability of the channel presumably reflects... 

Fusi F, Saponara S, Frosini M, Gorelli B, Sgaragli G. 2003. L-type Ca2 + channels activation and contraction elicited by myricetin on vascular smooth muscles. Naunyn Schmiedebergs Arch Pharmacol 368 470-478. 

Cao YQ, Tsien RW (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc Natl Acad Sci U S A 102 2590-2595. 

Walker D, Bichet D, Geib S, Mori E, Comet V, Snutch TP, Mori Y, De Waard M (1999) A new beta subtype-specific interaction in alphalA subunit controls P/Q-type Ca2+ channel activation. J Biol Chem 274 12383-12390. 

Inositol-1,4,5-triP Ca2 + -channel activation Phospholipase C on P-inositol... 

Phosphotidic acid Ca2 + -channel activation, adenylyl cyclase inhibition Phospholipase D products... 

Sims, C., and Harvey, R. D. 2004. Redox modulation of basal and beta-adrenergically stimulated cardiac L-type Ca2+ channel activity by phenylarsine oxide. Br. J. Pharmacol. 142 797-807. 

Thus, the possibility exists that Ca2+ channels are under dual control by stimulatory and inhibitory G proteins, as well as dual control by protein kinases. However, other explanations may apply. There may be more than one type of ACTH receptors on glomerulosa cells, one activating Gs, the other affecting Ca2+ channels activity by means independent of a G protein, such as activation of phospholipase A2 activity and/or formation of cGMP. Future research in this area should clarify this question. 

Takahashi, M., Tatsumi, M., Ohizumi, Y, and Yasumoto, T. 1983. Ca2+ channel activating function of maitotoxin, the most potent marine toxin known, in clonal rat pheochromocytoma cells. JB/c>/C/7ew 258, 10944-10949. 

As detailed in Sections 3.2-3.4, the G proteins involved in AR signaling (Fig. 7) include Gs, which couples (f-ARs to adenylyl cyclase stimulation, and Gi which mainly couples a2-ARs to AC inhibition. a2-ARs activation can also lead to Ca2+ channel activation via G0 coupling. For arARs, the Gq/11 family can mediate receptor coupling to phospholipase CP (PLC-p) activation. In addition, the atypical G protein Gh/TGase 2 can mediate PLC-yl activation by the a1B- and a1D-, but not a1A-, AR. 

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