Desensitization of the inhibition of the M-current in sympathetic neurons: Effects of ATP analogs, polyanions, and multiple agonist applications

Simmons, Mark A.; Becker, James B.; Mather, Robert J.

doi:10.1016/0896-6273(90)90113-t

Cited by 25 publications

(22 citation statements)

References 25 publications

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“…GTP-y-S would promote persistent G-protein activation (Pfaffinger, 1988;Elmslie et al, 1990) which would explain the progressive prolongation and reduction of muscarine responses. Furthermore, the progressive suppression of IM as more of the available pool of Gproteins became irreversibly activated would explain the observed run-down of IM seen only with ATP-y-S. Another explanation for prolongation of muscarine responses by ATP-y-S is that it inhibits the desensitization process (Simmons et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

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M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

Chen

Smith

1992

British J Pharmacology

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1The inward current and the M-current (IM) suppression produced when muscarine is applied to frog sympathetic ganglion cells was recorded by means of the whole-cell patch-clamp technique. The holding potential was -30 mV and [K+]. was 6 mM.2 The steady-state IM was maintained for at least 20min when the patch pipette contained neither adenosine 5'-triphosphate (ATP) nor adenosine 3':5'-cyclic monophosphate (cyclic AMP). Inclusion of these substances or the ATP antagonst, fiy-methyleneadenosine 5'-triphosphate (fy-MethATP; 1 or 2 nM) (failed to alter the rate of IM 'run down'. By contrast, inclusion of adenosine-5'-O-(3-thiotriphosphate) (ATP-y-S, 1 or 2 mM) resulted in a 60% reduction of the current within 18 min. 3 Despite the inability of ATP-y-S to maintain steady-state IM, it had no effect on the ability of muscarine (2-100pM) to suppress a constant fraction of the available current. ATP-y-S and fy-MethATP increased the rise time and duration of the response to muscarine. 4 Inclusion of a phosphatase inhibitor, diphosphoglyceric acid (DPG, 1-2.5 mM) or alkaline phosphatase (100 ypg ml -') failed to affect the amplitude of muscarinic responses. 5 These results question the role of the phosphorylation and/or dephosphorylation reactions in the transduction mechanism for muscarine-induced IM suppression but are consistent with the possibility that M-channels are 'directly coupled' via G-protein to the muscarinic receptor.

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Section: Discussionmentioning

confidence: 99%

“…Total GM at -30mV was estimated after digitallysubtracting the leak current predicted by the slope between -75 and -90 mV. In order to document the mean change in IM which occurred with time, IM (Simmons et al, 1990). Also, we have observed prolongation of agonist-induced responses when GTP-y-S is applied by this route (Selyanko et al, 1990).…”

Section: Methodsmentioning

confidence: 99%

M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

Chen

Smith

1992

British J Pharmacology

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“…A single-cell superfusion system was used for direct applications of wortmannin during whole cell recordings. Wortmannin was applied intracellularly by inclusion in the pipette solution as described previously (Simmons et al, 1990;Akasu et al, 1993).…”

Section: Whole-cell Recordingsmentioning

confidence: 99%

“…Membrane currents were recorded in the whole-cell configuration with methods described previously (Simmons et al, 1990;Tokimasa & Akasu, 1990a,b,c). The tip resistance of glass pipettes was 0.8-1.2 MO when filled with the pipette (internal) solution.…”

Section: Whole-cell Recordingsmentioning

confidence: 99%

Inhibition by wortmannin of M‐current in bullfrog sympathetic neurones

Tokimasa

Simmons

et al. 1995

British J Pharmacology

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1 The actions of wortmannin, an inhibitor of myosin light chain kinase (MLCK), on M-type potassium current of dissociated bullfrog sympathetic neurones have been examined. 2 The amplitude of M-current was measured by whole cell recordings from cells pretreated with wortmannin (0.01-10gM) or the wortmannin vehicle, dimethylsulphoxide (0.0001-0.1 vol%), for 30 min. Internal (recording pipette) solutions having three different pCa values (6, 7 and 8) were used for the measurements. 3 Irrespective of the pCa, M-current was not detectable when the cells were pretreated with 10 AM wortmannin. Wortmannin, 3 tLM, produced 85-95% inhibition of the M-current. Pretreatment with 10-30 nM wortmannin was without effect on M-current. 4 The M-current inhibition by wortmannin at concentrations of 0.1-1 gM depended on the pCa of the internal solution. Inhibition occurred only when the calcium-rich (pCa = 6) internal solution was used. 5 Pre-treatment of the cells with wortmannin (10 IM) did not affect rapidly-inactivating A-type or delayed rectifier-type potassium currents nor did it alter inwardly rectifying sodium-potassium current (IH)-6 These observations show that M-current inhibition by wortmannin has two pharmacological profiles. One is calcium-dependent and occurs at lower concentrations (0.1-1 LM), and is attributed to inhibition of MLCK by wortmannin. At higher concentrations (3-10 IM), wortmannin has an additional, calciumindependent action, inhibiting the M-current by an unknown mechanism.

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“…In addition to eliciting cell signaling responses such as inhibition of I M and increases in intracellular Ca 2ϩ , binding of substance P also leads to receptor desensitization in bullfrog sympathetic neurons (Jan and Jan, 1982;Simmons et al, 1990), in heterologous expression systems (Kwatra et al, 1993), and in vivo (Moochhala and Sawynok, 1984). To examine desensitization of the bullfrog SP receptor, CHO cells expressing the receptor were incubated in various concentrations of SP or the RTKs for 5 min.…”

Section: Concentration-response Curve For Inhibition Of the M-type Pomentioning

confidence: 99%

Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

Simmons¹

2006

J Pharmacol Exp Ther

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A cascade of events follows binding of an agonist ligand to the tachykinin NK 1 receptor. These events include activation of multiple signal transduction pathways as well as cellular modulation of receptor function by the process of desensitization. This study examines the differences in the abilities of naturally occurring peptide agonist ligands of the tachykinin NK 1 receptor to preferentially direct signaling through the receptor to produce signal activation versus receptor desensitization. The differential effects of tachykinin peptides with respect to ligand competition binding, receptor-G protein coupling, intracellular Ca 2ϩ elevations, and receptor desensitization have been measured. In relation to its potency in competition binding studies, substance P produces desensitization at lower concentrations, whereas higher concentrations are required to elicit a Ca 2ϩ response. In contrast to this, a related peptide, ranatachykinin C, is more effective at activating a Ca 2ϩ response relative to its ability to produce desensitization. This difference in functional selectivity is conserved for an amphibian and two mammalian ortholog tachykinin receptors. The present study demonstrates that peptide agonist ligands of NK 1 receptors can preferentially produce signal activation or desensitization.Over the years, the interactions of ligands with receptors have been classified as agonist interactions or antagonist interactions. Recently, it has become clear that a multitude of effects can follow binding of a ligand to a receptor (Kenakin, 2002(Kenakin, , 2003. These effects involve activation of multiple signal transduction pathways as well as cellular modulation of receptor function.One way that receptor function is modulated is by the process of desensitization. Desensitization occurs when the response to an agonist wanes in the continued presence of that agonist. Studies from our lab (Perrine et al., 2000) and from other labs (Vigna, 2001) have shown that the ability of a tachykinin receptor agonist ligand to produce signal activation and its ability to produce desensitization are not necessarily correlated.Our initial findings in this area showed that four different tachykinin peptides, substance P (SP), ranatachykinin (RTK) A, RTKB, and RTKC, could each activate the signal transduction pathways of the bullfrog SP receptor. For SP and RTKA, the concentrations required to produce desensitization of the receptor were two to four times less than the concentrations required to produce receptor activation. In contrast to this, the concentrations of RTKB and RTKC that produced desensitization were two times greater than the concentration needed to activate the signal transduction pathway.These data suggested that agonist ligands of the NK 1 receptor may exhibit functional selectivity. That is, agonists with the highest affinity and efficacy to activate a given signal transduction pathway do not also show the greatest degree of desensitization. This possibility seems particularly conceivable with respect to pep...

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Desensitization of the inhibition of the M-current in sympathetic neurons: Effects of ATP analogs, polyanions, and multiple agonist applications

Cited by 25 publications

References 25 publications

M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

Inhibition by wortmannin of M‐current in bullfrog sympathetic neurones

Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

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Desensitization of the inhibition of the M-current in sympathetic neurons: Effects of ATP analogs, polyanions, and multiple agonist applications

Cited by 25 publications

References 25 publications

M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation

Inhibition by wortmannin of M‐current in bullfrog sympathetic neurones

Functional Selectivity of NK1Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization

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Functional Selectivity of NK₁Receptor Signaling: Peptide Agonists Can Preferentially Produce Receptor Activation or Desensitization