[Possible molecular mechanisms of brain dysfunction in phenylketonuria]. / Vozmozhnye molekuliarnye mekhanizmy narushenii mozgovykh funktsii pri fenilketonurii.

Recent experimental data are summarized about changes in the functioning of calcium ion channels in clonal cellular lines (pheochromocytoma PC12) and hippocampal neurons of newborn rats on the background of altered intracellular level of aromatic amino acid L-tyrosine or its precursors L-phenylalanine. Elevation of the level of L-phenylalanine persistently down-regulated the high-threshold voltage-operated calcium channels in both types of cells without affecting the low-threshold ones in hippocampal neurons. This depression could be to some extent reversed by elevation of the level of L-tyrosine. Thus both amino acids seem to exert a long-lasting antagonistic modulatory effect on the corresponding channels, mediated probably through changes in tyrosylation of some cytoskeletal proteins. The participation of these molecular mechanisms in brain dysfunction during congenital disease phenylketonuria is suggested.

[Inhibition of the high-threshold calcium current in hippocampal neurons of rats subjected to intraperitoneal injection of phenylalanine]. / Podavlenie vysokoporogovogo kal'tsievogo toka v neironakh gippokampa krys, podvergnutykh intraperitonal'noi in"ektsii fenilalanina.

Effect of intraperitoneal injection of phenylalanine on the calcium current of hippocampal neurons of rats has been studied by the voltage clamp method of the whole-cell recordings. Calcium currents in hippocampal neurons of control animals after 5-7 days in culture can be separated into two components: low and high voltage-activated ones. The value of high voltage-activated calcium current was 69 +/- 13% at Vt = -10 mV from total calcium inward current in these neurons. High voltage-activated Ica in neurons of phenylalaninemic rats was significantly depressed and its value was 32 +/- 14%, the Vt value being the same. Low voltage-activated calcium current was resistant to intraperitoneal injection of L-phenylalanine.

[Effect of intracellular administration of L-tyrosine and L-phenylalanine on voltage dependent calcium current in PC 12 pheochromocytoma cells]. / Vliianie vnutrikletochnogo vvedeniia L-tirozina i L-fenilalanina na potentsialozavisimyi kal'tsievyi tok v kletkakh feokhromotsitomy PC 12.

Changes in the high-threshold calcium current (Ica) induced by intracellular administration of L-tyrosine and L-phenylalanine have been studied on internally perfused PC 12 pheochromocytoma cells using whole-cell voltage-clamp technique. L-tyrosine (20 microM/l) not only prevented a decay of Ica occurring during intracellular perfusion but induced also its transient recovery. In contrast, L-phenylalanine (20 microM/l) accelerated a decline of Ica. Replacement of ATP in the perfusing solution by an equivalent amount of ADP (2 mmol/l) did not alter the effect of amino acids. alpha-methyl-D, L-tyrosine (a specific blocker of tyrosine hydroxylase) caused the effect similar to that of L-tyrosine.

[Restoration of the potential-dependent L-phenylalanine-inhibited calcium current by L-tyrosine in cultured hippocampal neurons]. / Vosstanovlenie L-tirozinom potentsialozavisimogo kal'tsievogo toka, podavlennogo L-fenilalaninom, v kul'tiviruemykh neironakh gippokampa.

Calcium currents were recorded in cultured (5-7 days) hippocampal neurons isolated from one-day rats. The animals were intraperitoneally injected L-phenylalanine which induced in their brain biochemical changes typical of phenylketonuria. It has been found that in neurons from injected animals the amplitude of the high-threshold calcium current was substantially inhibited and amounted to 40 +/- 30% at Vt = +20 mV (amplitude of calcium currents at Vt = -10 mV taken as 100%). Addition of L-tyrosine to the cultivation medium (50 mumol/l) restored the high-voltage calcium current, its relative amplitude reaching 280 +/- 57%.

[Erythrocyte function in patients with complicated peptic ulcer]. / Funktsional'noe sostoianie éritrotsitov u bol'nykh s oslozhnennoi iazvennoi bolezn'iu.

A study of 63 patients with uncomplicated forms of ulcer of the duodenum revealed an increased aggregation activity of erythrocytes, reduction of their capacity to deformation, abnormal stability to oxygen hemolysis, increase of lipid peroxidation in erythrocytes. These disorders of the functional state of erythrocytes depended on the character of complication of the ulcer disease and are related to activation of the processes of lipid peroxidation. Antioxidant drugs are indicated.

[Pharmacologic and metabolic dependence of the delayed inactivated potassium outward current in the somatic membrane of snail neurons]. / Issledovanie farmakologicheskoi i metabolicheskoi zavisimosti zaderzhannogo inaktiviruiushchegosia kalievogo vykhodiashchego toka v somaticheskoi membrane neironov molliuskov.

Peculiarities of pharmacological and metabolic sensitivities of delayed potassium outward current depending on extracellular calcium ions (IK(Ca(out)) have been studied in experiments on isolated intracellularly perfused Helix neurons. It is shown that verapamil depresses the amplitude and accelerates the inactivation of this current. Blocking effect of verapamil increases with extracellular Ca2+ concentration. Functioning of IK(Ca(out)) channels depends on the intracellular metabolic processes. The current amplitude decreases during the neuron perfusion. Lowering of the intracellular solution temperature to +10 degrees C brings about the analogous result. Addition of ATP (2 mmol/l) and Mg2+ (3 mmol/l) to the intracellular perfusate prevents a decrease of potassium current; intracellular introduction of the exogenous protein kinase C restores the amplitude of this current. Polymyxin B (10(-4) mol/l), a blocker of protein kinase C, depresses the potassium current sensitive to extracellular calcium ions. The possible mechanism of Ca2+ action on IK(Ca(out)) through phosphatidyl-inositol metabolism is discussed.

[Blocking action of calmidazolium and chlorpromazine on the potassium outward current which depends on intracellular calcium ions]. / Blokiruiushchee deistvie kal'midazoliuma i khlorpromazina na kalievyi vykhodiashchii tok, zavisiashchii ot vnutrikletochnykh ionov kal'tsiia.

Effects of calmidazolium (R 24571) and chlorpromazine on the delayed potassium outward current in the somatic membrane were studied on nonidentified intracellularly perfused neurons of the snail Helix pomatia. Extracellular application of these substance evoked depression of the outward current. Inhibition of IK occurs at concentrations of calmodulin inhibitors 10(-9)-10(-8) mol/l. These agents inhibit primarily a component of the potassium current depending on the intracellular Ca2+ ions (IK(Ca in)). The inhibitory effect of these drugs can be explained by calmodulin-like structures of the receptor for intracellular calcium, providing modulation of IK(Ca in).

[Effect of extracellular potassium ions on the potassium outward current which depends on extracellular calcium ions]. / Deistvie vnekletochnykh ionov kaliia na kalievyi vykhodiashchii tok, zavisiashchii ot vnekletochnykh ionov kal'tsiia.

Changes in the delayed potassium outward current induced by introduction of K+ ions into extracellular solution have been studied in experiments on isolated intracellularly perfused Helix neurons. It is shown that extracellular administration of 5-10 mmol/l K+ ions into the solution produces a reversible increase of the potassium outward current which depends on the extracellular Ca2+ ions (IK(Ca out)). Extracellular potassium increases this component of the potassium current as a result of weakening of its inactivation.

[2 types of calcium-dependent outward potassium currents in the somatic membrane of Helix pomatia neurons]. / Dva tipa kal'tsiizavisimykh kanalov kalievogo vykhodiashchego toka v somaticheskoi membrane neironov vinogradnoi ulitki.

Peculiarities of delayed potassium outward current were studied in voltage clamp experiments on nonidentified intracellularly perfused neurons of the snail Helix pomatia. Together with voltage operated potassium currents which depend on the intracellular Ca2+ ions (IK(Cain], another peculiar calcium-dependent potassium current was shown to exist. This current increases with an increase of the external Ca2+ concentration (IK(Caout] and is insensitive to intracellular administration of EGTA and fluoride. It is blocked by extracellular application of cobalt ions (1.5 mmol/l). As distinct from (IK(Cain), IK(Caout] rapidly reaches a maximum and then inactivates to a steady-state level.

[Blocking of the Ca-dependent inward current in the somatic membrane of mollusk neurons by an elevated intracellular pH]. / Blokirovanie Ca-zavisimogo vykhodiashchego toka v somaticheskoi membrane neironov molliuskov povyshennym pH vnutrikletochnoi sredy.

The action of elevated intracellular pHi (pHi) on the transmembrane ionic currents in the somatic membrane was studied in intracellularly perfused nerve cells from Helix pomatia. Following a change in pHi from 7.3 to 9.0 the amplitude of potassium outward current recorded simultaneously with the calcium inward current was significantly reduced. This was accompanied by a shift of its I-V curve to more positive membrane potential values. In case of the calcium inward current blocking by external Cd2+ ions no reduction of the outward current was observed. Only a shift of its I-V curve along the potential axis remained. The calcium inward current was practically the same. It is suggested that the elevated pHi selectively blocks the Ca-dependent component of the potassium outward current.

[Inactivation of calcium channels in the somatic membrane of mollusk neurons]. / Inaktivatsiia kal'tsievykh tokov v somaticheskoi membrane neironov molliuskov.

The time-dependent decrease of calcium inward currents (inactivation) at long (about 1s) depolarizing membrane potential shifts was studied on isolated dialysed neurons of the mollusc Helix pomatia. It is shown that the time course of this decrease can be approximated by two exponents with corresponding time constants 20-70 and 250-350 ms. The fast component of the decay disappeared completely after pH increase of the intracellular solution to 8.5. The kinetics of the slow component did not change. A conclusion is made that the fast decay of the recorded current does not represent variations in the calcium current but is due to parallel activation of a nonspecific outward current whereas the slow decay represents true inactivation of the calcium current. It is shown that the inactivation velocity of this current is related to the maximal value of the latter but not to the level of membrane depolarization, and depends on conditions of accumulation of calcium ions at the inner surface of the cell membrane.