Effect of Forskolin on Voltage-Gated K
            <sup>+</sup>
            Channels Is Independent of Adenylate Cyclase Activation

Hoshi, Toshinori; Garber, Sarah S.; Aldrich, Richard W.

doi:10.1126/science.2454506

Cited by 245 publications

(107 citation statements)

References 25 publications

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“…Though this response was significantly smaller than without FSK (see Table 4, P<0.05), the combined response to FSK plus isoprenaline was not significantly different from that to isoprenaline alone (P>0.05). Forskolin has also been reported to block potassium channels (Hoshi et al, 1988;Cook, 1988), and this might be the origin of the complex influence of FSK.…”

Section: Hyperpolarization Is Mediated Via the F2-adrenoceptormentioning

confidence: 99%

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

Mil

Kerkhof

Heukelom

1995

British J Pharmacology

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1 The hyperpolarization of the resting membrane potential, V., induced by isoprenaline in the lumbrical muscle fibres of the mouse, was investigated by use of intracellular microelectrodes.2 In normal Krebs-Henseleit solution (potassium concentration: K+= 5.7 mM, 'control'), V. was -74.0±0.2 mV; lowering K+ to 0.76 mM ('low K'7) resulted in either a hyperpolarization (VM -95.7± 2.9 mV), or a depolarization (Vm= -52.0± 0.3 mV). When Vm hyperpolarized after switching to low K', the addition of isoprenaline resulted in increased hyperpolarization Vm: AVm=-16.3 + 3.2 mV to a final Vm=-110.1I±3.4 mV. Adding iso-prenaline when Vm depolarized in low K+, leads to a hyperpolarization of either by -11.6 ± 0.5 mV to -63.6+0.8 mV or by -51.7+2.7 mV to -106.9±3.9 mV. 5 Ouabain (0.1 to 1 mM) did not suppress the hyperpolarization by isoprenaline in 5.7 mM K + (AVm=-6.7±0.4 mV) or the hyperpolarization of the depolarized cells in low K + (AVm= 9.7 ±1.5 mV). 6The hyperpolarization is a logarithmically decreasing function of K + in the range between 2 and 20 mM (12 mV/decade). 7 IBMX and 8Br-cyclic AMP mimicked the response to isoprenaline whereas forskolin (FSK) induced in low K + a hyperpolarization of -7.0±0.7 mV that could be augmented by addition of isoprenaline (AVm -8.2± 1.8 mV). 8In control and low K+, Ba2`(0.6 mM) inhibited the hyperpolarization induced by isoprenaline, IBMX or 8Br-cyclic AMP. Other blockers of the potassium conductance such as TEA (5 mM) and apamin (0.4 riM) had no effect. 9 We conclude that in the lumbrical muscle of the mouse the isoprenaline-induced hyperpolarization is primarily due to an increase in potassium permeability.

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Section: Hyperpolarization Is Mediated Via the F2-adrenoceptormentioning

confidence: 99%

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

Mil

Kerkhof

Heukelom

1995

British J Pharmacology

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“…In addition to its ability to increase intracellular levels of cAMP through direct activation of adenylyl cyclase, forskolin has also been shown to affect certain cellular processes through a mechanism that does not involve production of cAMP (Joost and Steinfelder, 1987;Hoshi et al, 1988;Laurenza et al, 1989;Beavo and Reifsnyder, 1990). To determine if the inhibitory effect of forskolin on DNA synthesis is mediated via cAMP, we treated Reh cells with 3-isobutyl-1-methylxanthine (IBMX), cholera toxin (CTX), and 8-CPTcAMP.…”

Section: Inhibition Of Dna Synthesis By Forskolin Is Mediated Via Campmentioning

confidence: 99%

cAMP-mediated Inhibition of DNA Replication and S Phase Progression: Involvement of Rb, p21^Cip1, and PCNA

Naderi

Wang

Chen³

et al. 2005

MBoC

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cAMP exerts an antiproliferative effect on a number of cell types including lymphocytes. This effect of cAMP is proposed to be mediated by its ability to inhibit G1/S transition. In this report, we provide evidence for a new mechanism whereby cAMP might inhibit cellular proliferation. We show that elevation of intracellular levels of cAMP inhibits DNA replication and arrests the cells in S phase. The cAMP-induced inhibition of DNA synthesis was associated with the increased binding of p21Cip1 to Cdk2-cyclin complexes, inhibition of Cdk2 kinase activity, dephosphorylation of Rb, and dissociation of PCNA from chromatin in S phase cells. The ability of cAMP to inhibit DNA replication and trigger release of PCNA from chromatin required Rb and p21Cip1 proteins, since both processes were only marginally affected by increased levels of cAMP in Rb Ϫ/Ϫ and p21 Cip1Ϫ/Ϫ 3T3 fibroblasts. Importantly, the implications of cAMP-induced inhibition of DNA synthesis in cancer treatment was demonstrated by the ability of cAMP to reduce apoptosis induced by S phase-specific cytotoxic drugs. Taken together, these results demonstrate a novel role for cAMP in regulation of DNA synthesis and support a model in which activation of cAMP-dependent signaling protects cells from the effect of S phase-specific antitumor agents. INTRODUCTIONThe second messenger cyclical AMP (cAMP) plays an important role in regulation of numerous cellular functions. Elevation of intracellular cAMP levels either stimulates or inhibits proliferation of cells depending on the cell type (Pastan et al., 1975;Dumont et al., 1989). Generally, cAMP has an antiproliferative effect on most cells of mesenchymal origin (Blomhoff et al., 1988;Dugan et al., 1999). We have observed that increase in intracellular cAMP leads to accumulation of lymphoid cells in the G1 phase and correlates with rapid dephosphorylation of the retinoblastoma tumor suppressor protein (Rb;Blomhoff et al., 1987Blomhoff et al., , 1988Christoffersen et al., 1994;Naderi and Blomhoff, 1999;Gutzkow et al., 2002). Furthermore, this antiproliferative effect of cAMP in lymphocytes has been shown to be mediated through protein kinase A type I (Skalhegg et al., 1992;Tasken et al., 1994).Rb, is an important inhibitor of cell cycle progression (Wang et al., 1994;Harbour and Dean, 2000). In its hypophosphorylated active form, Rb inhibits transition of cells from G1 into S phase of the cell cycle. In addition, Rb has also been shown to negatively regulate DNA replication and block S phase progression (Chew et al., 1998;Knudsen et al., 1998). The negative effect of Rb on cell cycle progression is countered by its phosphorylation by cyclin-dependent kinases (Cdks). When complexed to their regulatory cyclin subunits, Cdks phosphorylate and thereby inactivate the antiproliferative function of Rb (Mittnacht, 1998). Specifically, inactivation of Rb in G1 is achieved through its sequential phosphorylation by Cdk4/6-cyclin D, Cdk2-cyclin E, and Cdk2-cyclin A complexes (Zarkowska and Mittnacht, 1997;Lundberg and Weinberg...

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“…Recent reports have shown that the modulation of ion channels and the neurotropic actions of forskolin may be independent of the adenylate cyclase-cyclic AMP system (Hoshi, Garber & Aldrich, 1988;Wagoner & Pallotta, 1988;Wakade et al 1990 b). However, in the present study we establish a direct involvement of cyclic AMP in the modulation of sympathetic transmitter release.…”

Section: Neuronal Blockers Do Not Alter Transmembrane Ca2+ Currentsmentioning

confidence: 99%

Dissociation between intracellular Ca2+ and modulation of [3H]noradrenaline release in chick sympathetic neurons.

Przywara

Bhave

et al. 1991

The Journal of Physiology

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SUMMARY1. We studied the relation between cyclic AMP, intracellular Ca2" concentration and release of [3H]noradrenaline ([3H]NA) in sympathetic neurons cultured from chick embryos.2. Forskolin (10 ,tM) and vasoactive intestinal polypeptide (VIP, 3/M) increased cellular levels of cyclic AMP 8-and 3-fold, respectively, either in the absence or presence of electrical stimulation. Electrical stimulation (1 Hz for 10 s) alone had no effect on cyclic AMP levels.3. Electrically evoked (1 Hz for 10 s) release of [3H]NA was facilitated by 10 ,tMforskolin, 3 1um-VIP and by the non-hydrolysable cyclic AMP analogue, 8-bromoadenosine 3': 5'-cyclic monophosphate (8-Br-cyclic AMP). The inactive analogue of forskolin, dideoxyforskoli-n, had no effect on [3H]NA release.4. The stimulation-evoked release of [3H]NA was completely inhibited by the neuronal blocking drugs guanethidine (1 /M) and bretylium (3 /tm).5. Whole-cell voltage-clamp studies showed that forskolin and VIP did not facilitate and guanethidine and bretylium did not block voltage-activated Ca2" currents in the cell bodies of sympathetic neurons.6. Fluorescence measurements using the Ca2"-sensitive dye Indo-1 revealed that forskolin and guanethidine had no effect on the electrically stimulated increase in intracellular Ca2+ concentration recorded from the cell bodies and the growth cones.7. We conclude that release of [3H]NA can be enhanced or blocked without affecting the increase in intracellular Ca2+ concentration produced by electrical stimulation. Therefore, it is possible that pharmacological agents enhance or depress the release of [3H]NA by acting on steps of exocytosis that are down-stream from Ca2`mobilization.

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Effect of Forskolin on Voltage-Gated K ⁺ Channels Is Independent of Adenylate Cyclase Activation

Cited by 245 publications

References 25 publications

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

cAMP-mediated Inhibition of DNA Replication and S Phase Progression: Involvement of Rb, p21^Cip1, and PCNA

Dissociation between intracellular Ca2+ and modulation of [3H]noradrenaline release in chick sympathetic neurons.

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Effect of Forskolin on Voltage-Gated K + Channels Is Independent of Adenylate Cyclase Activation

Cited by 245 publications

References 25 publications

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

Modulation of the isoprenaline‐induced membrane hyperpolarization of mouse skeletal muscle cells

cAMP-mediated Inhibition of DNA Replication and S Phase Progression: Involvement of Rb, p21Cip1, and PCNA

Dissociation between intracellular Ca2+ and modulation of [3H]noradrenaline release in chick sympathetic neurons.

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Effect of Forskolin on Voltage-Gated K ⁺ Channels Is Independent of Adenylate Cyclase Activation

cAMP-mediated Inhibition of DNA Replication and S Phase Progression: Involvement of Rb, p21^Cip1, and PCNA