Long-chain CoA esters activate human pancreatic beta-cell KATP channels: potential role in Type 2 diabetes.
OBJECTIVE
The ATP-regulated potassium (KATP) channel in the pancreatic beta cell couples the metabolic state to electrical activity. The primary regulator of the KATP channel is generally accepted to be changes in ATP/ADP ratio, where ATP inhibits and ADP activates channel activity. Recently, we showed that long-chain CoA (LC-CoA) esters form a new class of potent KATP channel activators in rodents, as studied in inside-out patches.


METHODS
In this study we have investigated the effects of LC-CoA esters in human pancreatic beta cells using the inside-out and whole-cell configurations of the patch clamp technique.


RESULTS
Human KATP channels were potently activated by acyl-CoA esters with a chain length exceeding 12 carbons. Activation by LC-CoA esters did not require the presence of Mg2+ or adenine nucleotides. A detailed characterization of the concentration-dependent relationship showed an EC50 of 0.7+/-0.1 micromol/l. Furthermore, in the presence of an ATP/ADP ratio of 10 (1.1 mmol/l total adenine nucleotides), whole-cell KATP channel currents increased approximately six-fold following addition of 1 micro mol/l LC-CoA ester. The presence of 1 micro mol/l LC-CoA in the recording pipette solution increased beta-cell input conductance, from 0.5+/-0.2 nS to 2.5+/-1.3 nS.


CONCLUSIONS
Taken together, these results show that LC-CoA esters are potent activators of the KATP channel in human pancreatic beta cells. The fact that LC-CoA esters also stimulate KATP channel activity recorded in the whole-cell configuration, points to the ability of these compounds to have an important modulatory role of human beta-cell electrical activity under both physiological and pathophysiological conditions.
Bränström
R
R
Rolf Luft Center for Diabetes Research, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. robert.branstrom@ks.se
Aspinwall
C A
CA
Välimäki
S
S
Ostensson
C-G
CG
Tibell
A
A
Eckhard
M
M
Brandhorst
H
H
Corkey
B E
BE
Berggren
P-O
PO
Larsson
O
O
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D015636:Magnesium Chloride / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology*; D019301:Oleic Acid / Q000494:pharmacology; D010171:Palmitoyl Coenzyme A / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels
D000214:Acyl Coenzyme A; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D015636:Magnesium Chloride; D010171:Palmitoyl Coenzyme A; D019301:Oleic Acid; D000244:Adenosine Diphosphate; C050466:lauroyl-coenzyme A; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide