Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors / 神经科学通报·英文版

Adenosine triphosphate (ATP) is well-known as a universal source of energy in living cells. Less known is that this molecule has a variety of important signaling functions: it activates a variety of specific metabotropic (P2Y) and ionotropic (P2X) receptors in neuronal and non-neuronal cell membranes. So, a wide variety of signaling functions well fits the ubiquitous presence of ATP in the tissues. Even more ubiquitous are protons. Apart from the unspecific interaction of protons with any protein, many physiological processes are affected by protons acting on specific ionotropic receptors-acid-sensing ion channels (ASICs). Both protons (acidification) and ATP are locally elevated in various pathological states. Using these fundamentally important molecules as agonists, ASICs and P2X receptors signal a variety of major brain pathologies. Here we briefly outline the physiological roles of ASICs and P2X receptors, focusing on the brain pathologies involving these receptors.

Nitric oxide modulates ATP-evoked currents in mouse Leydig cells

Testosterone synthesis within Leydig cells is a calcium-dependent process. Intracellular calcium levels are regulated by different processes including ATP-activated P2X purinergic receptors, T-type Ca2+ channels modulated by the luteinizing hormone, and intracellular calcium storages recruited by a calcium-induced calcium release mechanism. On the other hand, nitric oxide (NO) is reported to have an inhibitory role in testosterone production. Based on these observations, we investigated the interaction between the purinergic and nitrergic systems in Leydig cells of adult mice. For this purpose, we recorded ATP-evoked currents in isolated Leydig cells using the whole cell patch clamp technique after treatment with L-NAME (300 μM and 1 mM), L-arginine (10, 100, 300, and 500 μM), ODQ (300 μM), and 8-Br-cGMP (100 μM). Our results show that NO produced by Leydig cells in basal conditions is insufficient to change the ATP-evoked currents and that extra NO provided by adding 300 μM L-arginine positively modulates the current through a mechanism involving the NO/cGMP signaling pathway. Thus, we report an interaction between the nitrergic and purinergic systems in Leydig cells and suggest that Ca2+ entry via the purinergic receptors can be regulated by NO.

Purinergic signalling: past, present and future

The discovery of non-adrenergic, non-cholinergic neurotransmission in the gut and bladder in the early 1960's is described as well as the identification of adenosine 5'-triphosphate (ATP) as a transmitter in these nerves in the early 1970's. The concept of purinergic cotransmission was formulated in 1976 and it is now recognized that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. Two families of receptors to purines were recognized in 1978, P1 (adenosine) receptors and P2 receptors sensitive to ATP and adenosine diphosphate (ADP). Cloning of these receptors in the early 1990's was a turning point in the acceptance of the purinergic signalling hypothesis and there are currently 4 subtypes of P1 receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of G protein-coupled receptors. Both short-term purinergic signalling in neurotransmission, neuromodulation and neurosecretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation, motility, death in development and regeneration are recognized. There is now much known about the mechanisms underlying ATP release and extracellular breakdown by ecto-nucleotidases. The recent emphasis on purinergic neuropathology is discussed, including changes in purinergic cotransmission in development and ageing and in bladder diseases and hypertension. The involvement of neuron-glial cell interactions in various diseases of the central nervous system, including neuropathic pain, trauma and ischemia, neurodegenerative diseases, neuropsychiatric disorders and epilepsy are also considered.

P2X1 receptors and the endothelium

Adenosine triphosphate (ATP) is now established as a principle vaso-active mediator in the vasculature. Its actions on arteries are complex, and are mediated by the P2X and P2Y receptor families. It is generally accepted that ATP induces a bi-phasic response in arteries, inducing contraction via the P2X and P2Y receptors on the smooth muscle cells, and vasodilation via the actions of P2Y receptors located on the endothelium. However, a number of recent studies have placed P2X1 receptors on the endothelium of some arteries. The use of a specific P2X1 receptor ligand, alpha, beta methylene ATP has demonstrated that P2X1 receptors also have a bi-functional role. The actions of ATP on P2X1 receptors is therefore dependant on its location, inducing contraction when located on the smooth muscle cells, and dilation when expressed on the endothelium, comparable to that of P2Y receptors.

Extracellular ATP in the lymphohematopoietic system: P2Z purinoceptors and membrane permeabilization

The effects of extracellular nucleosides and nucleotides on many organs and systems have been recognized for almost 50 years. The effects of extracellular ATP (ATP(o)), UTP (o), ADP(o), and other agonists are mediated by P2 purinoceptors. One of the most dramatic effects of ATP(o) is the permeeabilization of plasma membranes to low molecular mass solutes of up to 900 Da. This effect is evident in several cells of the lymphohematopoietic system and is supposed to be mediated by P2Z, and APT(4-) -activated purinoceptor. Here, we review some basic information concerning P2 purinoceptors and focus our attention on P2Z-associated phenomena displayed by macrophages. Using fluorescent dye uptake, measurement of free intracellular Ca2+ concentration and electrophysiological recordings, we elucidate some of the events that follow the application of ATP to the extracellular surface of macrophages. We propose a regulatory mechanism for the P2Z-associated permeabilization pore. The presence of P2 purinoceptors in cells of the lymphohematopoietic system makes them potential candidates to mediate immunoregulatory events.

Efecto del tolueno en el desarrollo neuronal de crías de rata, cuyas madres fueron expuestas a inhalación crónica durante gestación o durante su adolescencia / Effects of the neural development of rat pups whose moters were exposed to toluene via chronic inhalation either during pregnancy or adolescence

Desarrollo neuronal en crios de rata adolescentes y gestantes expuestas a inhalación crónica de tolueno. Se sometieron a inhalación de tolueno a tres ratas jóvenes de 70 días de edad y nueve ratas gestantes de 90 días de edad durante 15 minutos por día desde la cruza hasta un día antes de la fecha de parto. Las ratas jóvenes se cruzaron después del período de inhalación con machos que no inhalaron el solvente. Las crias de las hembras tratadas, así como las de un grupo testigo fueron sometidas a iguales condiciones pero sin tolueno. Fueron sacrificadas por perfusión intracardíaca 24 crias de cada grupo, 12 de 14 días y 12 de 21 días de edad. Fue cuantificado el grado de ramificación de los procesos neuronales de las neuronas piramidales de la V capa de la corteza visual impregnadas con el método rápido de Golgi. Se encontró decremento significativo en las ramificaciones en la porción distal de la dendrita principal en los grupos expuestos al solvente comprarados con los grupos testigo y control

Isquemia silenciosa del miocardio: etiologia / Silent myocardial ischemia: etiology

La isquemia del miocardio es un desequilibrio entre el consumo y la produccion de trifosfato de adenosin que termina en una deplecion de ATP seguida por una cascada de eventos bioquimicos. No se ha establecido por que unos pacientes presetan dolor durante estos eventos y otros no, pero diversos estudios indican que la explicacion puede residir en una combinacion del umbral de dolor y la magnitud de la isquemia. Esta ultima puede ocurrir durante el ejercicio energetico o durante actividades cotidianas o puede ocurrir en reposo e incluso ser influenciada por la tension emocional. Es mas comun que suceda en las horas de la manana, tal vez porque la frecuencia cardiaca, la presion sanguinea y la contractilidad suben rapidamente en la manana y los factores que aumentan el tono de los vasos y reducen el flujo sanguieno tambien se elevan durante estas horas

Effect of extracellular pH and DNFB treatment on the mechanical performance of frog skeletal muscle.

isometric tension and maximum velocity of shortening of frog sartorious and biceps muscles were measured at varying pH and compared with the values obtained for muscles treated with DNFB. Both To and Vmax exhibited increase with increase in pH above neutral pH upto pH 9, and decreased as the pH was decreased up to 5. Muscle treated with DNFB at pH 7 showed about 30% decrement but these too improved at pH 9 to almost 105% and 130% respectively compared to untreated muscle at pH 7. Using the number of short duration tetanic contractions, which reduce To and Vmax by half, as an index for the onset of fatigue, high pH was found to have a positive effect in both normal and DNFB-treated muscle. Thus, the crucial factor for onset of fatigue is not a fall in ATP level but acidification and treatment with high pH Ringer's solution partially annuls the effect of acidosis, arising either naturally or from DNFB treatment. One additional role of creatine kinase activity to that of ATP regeneration is suggested to be the maintenance of neutral pH in the sarcoplasm.