a little more info on DNP...
Ion channels are membrane proteins that control the flux of ions across an otherwise impermeable cell membrane. Potassium (K) channels were first decribed by Noma [1] in 1983, and later in 1991 the ATP-sensitive K channel (KATP) was described by the same researcher [2]. Potassium channels determine cell membrane potential.
KATP channels exist in most excitable cells. They are regulated by the intracellular level of ATP as well as by various nucleotide diphosphates, pH and lactate concentrations. The activity of KATP channels is inhibited by increasing the intracellular ATP concentration. Closure of these channels in response to glucose metabolism depolarises the cell, stimulating voltage-dependent electrical activity, and calcium ion (Ca) entry. In the pancreatic beta cells, an increase in blood sugar level leads to an elevated ATP/ADP ratio, which in turn inhibits KATP channels, so as to alter the membrane potential and cause insulin release. It is accompanied by increases in respiratory rate, pyridine and flavin nucleotide reduction state, and intracellular pH [3].
Thus, the KATP channel couples nutrient metabolism to the membrane potential.
o Increase in blood glucose -> increase in glucose metabolism -> increase in intracell ATP -> inhibition of KATP channel.
o Channel CLOSED: cell depolarized, Ca++ uptake, insulin exocytosis.
KATP channels play an important role in the control of vascular tone [4]. Polarization following potassium channel activation (opening) results in lessened calcium influx and smooth muscle relaxation.
o KATP channel BLOCKED -> vascular tone increases.
o KATP channel ACTIVATED -> vascular tone decreases.
Besides being regulated by intracellular signals, potassium channels may also be regulated by membrane potential. Thus, in excitable cells in the heart, muscle, and nervous system, voltage-gated potassium channels are activated during an action potential; the activities of these potassium channels determine to a large extent the shape of the action potential, hence the strength of the signaling.
o KATP BLOCKED -> more strength
o KATP ACTIVATED -> less strength
Drugs which block KATP channels: tolbutamide, glyburide, glibenclamide.
Drugs which activate KATP channels: Prostaglandin E2 and I2, adenosine,
lemakalim.
Drugs which activate K channels: pinacidil, cromakalim.
Mitochondria also contain a K+ channel that causes rapid K+ uptake when open [5].
DNP
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What happens when someone takes the decoupler dinitrophenol (DNP)? Blood glucose will result in increased metabolism, but the level of ATP in the cell does not increase! In fact, it is depleted. So in this case, the KATP channel is not inhibited, and it stays open. Calcium is not taken into the cell, and insulin is not released. The person taking DNP has in effect given himself temporary diabetes.
Insulin is needed to facilitate the uptake of glucose into cardiac, skeletal, and adipose tissue, and to convert glucose to glycogen in the liver. It is anti-proteolytic and protects against the various ailments commonly seen in diabetics, such as vision problems and polyneuropathy. Not coincidentally, the same problems can result from ingesting DNP.
This is why, when one takes DNP, one also needs to take exogenous insulin.
Since the KATP channel remains open, vascular and muscular tone relax. Probably blood pressure will decrease. Strength will diminish.
It would seem that an antidote for DNP might be anything that causes the KATP channel to close, for example the drug glibenclamide.
References:
1. Noma A. 1983. Nature 305: 147.
2. Noma A, Takano M. 1991. The ATP-sensitive K+ channel. Jpn J Physiol 41(1):77-87.
3. Civelek VN, Deeney JT, et al. 1996. Temporal sequence of metabolic and ionic events in glucose-stimulated clonal pancreatic-cells. Biochem. J. 315: 1015-1019. Boston University Medical Center.
4. Nichols, C.G. and Lederer, W.J. 1991. ATP-sensitive potassium channels in the cardiovascular system. American Journal of Physiology 261:H1675-H1686.
5. Paucek, P, Mironova, G, et al. 1992 "Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K+ channel from rat liver and beef heart mitochondria," J. Biol. Chem. 267, 26062.
6. Nakamura S. 1989. Glucose reverses DNP induced changes in action potentials. Cardiovascular Res. 23(4):286-294.