Compounds related to carnitine have been applied iontophoretically from five-barrelled micropipettes to neurons of the cerebral cortex of anesthetized cats. Both optically active and racemic mixtures of carnitine, acetyl carnitine, carnitine nitrile, and acetylcarnitylcholine had an excitatory action on cells excited by acetylcholine. The levorotatory forms were generally, but not invariably, stronger excitants than their enantiomers. Atropine administered intravenously blocked the action of all carnitines and acetylcholine. These derivatives (like ACh itself) had a depressant effect on some cells which were not excited by ACh.
Choline esters of spin-labeled fatty acids (long-chain acylcholines) were used to probe the hydrophobic environment of the acetylcholine receptor protein in membrane fragments from Torpedo marmorata. These spin-labels competitively inhibit the binding of [3H]acetylcholine to the receptor site. Their inhibition constants (KI) were close to 200 nM. At the high membrane concentration required for electron spin resonance (ESR) experiments, the apparent inhibition constants (KIapp) differed from KI determined by using dilute membrane concentration. This is due to the amphiphilic character of long-chain acylcholine. For most spin-labels used, only difference ESR spectroscopy provided reliable spectra corresponding to receptor-bound spin-labeled acylcholines. Acetylcholine receptor agonists and antagonists displaced the acylcholine from the receptor sites, whereas choline had only a weak effect. This produced a modification in the ESR spectra of the bound acylcholines and provided evidence that the acylcholines bound to the receptor sites in a specific manner. The interpretation of the spectra of receptor-bound spin-labels favored a strong barrier to the motion of the probe when attached to the middle of the acyl chain. However, when the probe was close to the methyl terminal of a stearoylcholine molecule a much greater fluidity was found. Short-range spin-spin interactions were created between spin-labels bound to the receptor site and spin-labels in a fluid phase. This indicates that lipids next to the receptor protein are not completely immobilized in spite of the semicrystalline organization of the proteins in the postsynaptic region.
SUMMARYCa2 + and Mg2 + released from five-barrelled micropipettes by currents of 5 to 80 nA caused a deceleration of the firing rate of neurones discharging spontaneously, or excited by the simultaneous administration of glutamate or acetylcholine, in the cerebral cortex, cuneate nucleus and spinal cord. Excitation of cells in the cuneate nucleus, caused by stimulation of sense organs, was also suppressed by Ca2+ and Mgz+. Synaptic transmission of volleys, evoked by electrical stimulation, from thalamus to cortical cells, from superficial radial nerve to cells in the cuneate nucleus, and from ventral root via recurrent collaterals to Renshaw cells, was partially or completely blocked by Ca2 + and Mg2+ (60 to 200 nA). When given together, the depressant effect of the two ions summed. There was no evidence of enhanced synaptic transmission under the influence of Ca2+. It is concluded that in the central nervous system a small elevation of the concentration of Ca2 + or of Mg2 + has a powerful postsynaptic depressant effect.
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