PMID- 8012711
OWN - NLM
STAT- MEDLINE
DCOM- 19940725
LR  - 20190512
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 111
IP  - 1
DP  - 1994 Jan
TI  - Interaction of tolbutamide and cytosolic nucleotides in controlling the 
      ATP-sensitive K+ channel in mouse beta-cells.
PG  - 302-10
AB  - 1. In mouse pancreatic beta-cells the role of cytosolic nucleotides in the 
      regulation of the sulphonylurea sensitivity of the adenosine 
      5'-triphosphate-sensitive K+ channel (KATP-channel) was examined. Patch-clamp 
      experiments with excised inside-out membrane patches were carried out using an 
      experimental protocol favouring phosphorylation of membrane proteins. 2. In the 
      absence of Mg2+, the KATP-channel-inhibiting potency of cytosolic nucleotides 
      decreased in the order ATP = adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) > 
      adenosine 5'-diphosphate (ADP) > adenosine 5'-O-(2-thiodiphosphate) (ADP beta S) 
      = adenylyl-imidodiphosphate (AMP-PNP) > 2'-deoxyadenosine 5'-triphosphate (dATP) 
      > uridine 5'-triphosphate (UTP) > 2'-deoxyadenosine 5'-diphosphate (dADP) > 
      guanosine 5'-triphosphate (GTP) > guanosine 5'-diphosphate (GDP) > uridine 
      5'-diphosphate (UDP). 3. In the presence of Mg2+, the inhibitory potency of 
      cytosolic nucleotides decreased in the order ATP gamma S > ATP > AMP-PNP > ADP 
      beta S > dATP > UTP. In the presence of Mg2+, the KATP-channels were activated by 
      dADP, GTP, GDP and UDP. 4. Tolbutamide inhibited the KATP-channels not only in 
      the presence but also in the prolonged absence of Mg2+. In nucleotide-free 
      solutions, the potency of tolbutamide was very low. When about half of the 
      KATP-channel activity was inhibited by ATP, AMP-PNP, ADP beta S or ADP (absence 
      of Mg2+), the potency of tolbutamide was increased. 5. Tolbutamide (100 microM) 
      slightly enhanced the channel-inhibiting potency of AMP-PNP and inhibited the 
      channel-activating effect of MgGDP in a non-competitive manner. 6. Channel 
      activation by MgGDP (0.5 mM) competitively antagonized the inhibitory responses 
      to AMP-PNP (1 MicroM- 1 mM). This effect of GDP was neutralized by tolbutamide 
      (100 MicroM).7. The stimulatory effect of 0.5 mM MgGDP was neutralized by 200 
      MicroM AMP-PNP. Under these conditions the potency of tolbutamide was much higher 
      than in the presence of 0.5 mM MgGDP alone or in the absence of any 
      nucleotides.8. dADP (0.3-1 mM) increased the potency of tolbutamide. Additional 
      application of 200 MicroM AMPPNP caused a further increase in the potency of 
      tolbutamide.9. In conclusion, in the simultaneous presence of inhibitory and 
      stimulatory nucleotides, binding of sulphonylureas to their receptor causes 
      direct inhibition of channel activity, non-competitive inhibition of the action 
      of stimulatory nucleotides and interruption of the competitive interaction 
      between stimulatory and inhibitory nucleotides. The latter effect increases the 
      proportion of KATP- channels staying in the nucleotide-blocked state. In 
      addition, this state potentiates the direct effect of sulphonylureas.
FAU - Schwanstecher, C
AU  - Schwanstecher C
AD  - Institute of Pharmacology & Toxicology, University of Gottingen, Germany.
FAU - Dickel, C
AU  - Dickel C
FAU - Panten, U
AU  - Panten U
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Adenine Nucleotides)
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Potassium Channels)
RN  - 0 (Uracil Nucleotides)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 982XCM1FOI (Tolbutamide)
RN  - I38ZP9992A (Magnesium)
SB  - IM
MH  - Adenine Nucleotides/*pharmacology
MH  - Adenosine Triphosphate/metabolism/pharmacology
MH  - Animals
MH  - Cells, Cultured
MH  - Electrophysiology
MH  - Guanine Nucleotides/*pharmacology
MH  - Islets of Langerhans/drug effects/*metabolism
MH  - Magnesium/pharmacology
MH  - Male
MH  - Mice
MH  - Phosphorylation
MH  - Potassium Channels/drug effects/*metabolism
MH  - Tolbutamide/metabolism/*pharmacology
MH  - Uracil Nucleotides/*pharmacology
PMC - PMC1910016
EDAT- 1994/01/01 00:00
MHDA- 1994/01/01 00:01
PMCR- 1995/01/01
CRDT- 1994/01/01 00:00
PHST- 1994/01/01 00:00 [pubmed]
PHST- 1994/01/01 00:01 [medline]
PHST- 1994/01/01 00:00 [entrez]
PHST- 1995/01/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.1994.tb14060.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 1994 Jan;111(1):302-10. doi: 10.1111/j.1476-5381.1994.tb14060.x.