omega-agatoxin-iva and Phenylketonurias

Ca2+ channels expressed in Xenopus oocytes using mRNA purified from the brain of the rats subjected to chronic treatment with l-phenylalanine in order to model conditions typical for the congenital disease called phenylketonuria (PKU) were studied using double microelectrode technique. The amplitude of Ca2+ channel currents (IBa, 40 mM Ba2+ as a charge carrier) directed in the oocytes by mRNA from the brain of the animals with model PKU was significantly smaller compared to the control animals (145+/-23 nA vs. 270+/-38 nA, p<0.025) while the voltage-dependence of both currents was similar and typical for that of high voltage-activated (HVA) Ca2+ channels. No evidence for the expression of low voltage-activated Ca2+ channels were found. The decrease of the overall HVA Ba2+ current under model PKU occurred primarily at the expense of the decaying, omega-conotoxin-sensitive component which accounted for about 64% of the total current amplitude in control, and apparently was associated with the activity of the expressed N-type Ca2+ channels. omega-Aga-IVA-sensitive, P/Q component of IBa that contributed not more than 10% to the total current in control showed no change under PKU conditions. In addition to the decreased amplitude, Ba2+ current from model PKU animals showed accelerated run-down during prolonged recording (50%/h compared to 15%/h in control). Our data suggest that hyperphenylalaninemic conditions affect the expression of preferentially N-type Ca2+ channels via the reduction of their specific mRNA content as well as influence the type and manner of channels regulation. The underexpression of N-type Ca2+ channels is consistent with the decrease in the overall number of synaptic contacts during PKU and may be one of the factors contributing to the severe damage of the brain function.

Topics: Animals; Brain Chemistry; Cadmium; Calcium Channel Blockers; Calcium Channels; Electrophysiology; Ion Channel Gating; omega-Agatoxin IVA; omega-Conotoxin GVIA; Oocytes; Peptides; Phenylalanine; Phenylketonurias; Rats; RNA, Messenger; Spider Venoms; Xenopus