RESUMO
Purinergic receptors regulate the processing of neural information in the hippocampus and cerebral cortex, structures related to cognitive functions. These receptors are activated when astrocytic and neuronal populations release adenosine triphosphate (ATP) in an autocrine and paracrine manner, following sustained patterns of neuronal activity. The modulation by these receptors of GABAergic transmission has only recently been studied. Through their ramifications, astrocytes and GABAergic interneurons reach large groups of excitatory pyramidal neurons. Their inhibitory effect establishes different synchronization patterns that determine gamma frequency rhythms, which characterize neural activities related to cognitive processes. During early life, GABAergic-mediated synchronization of excitatory signals directs the experience-driven maturation of cognitive development, and dysfunctions concerning this process have been associated with neurological and neuropsychiatric diseases. Purinergic receptors timely modulate GABAergic control over ongoing neural activity and deeply affect neural processing in the hippocampal and neocortical circuitry. Stimulation of A2 receptors increases GABA release from presynaptic terminals, leading to a considerable reduction in neuronal firing of pyramidal neurons. A1 receptors inhibit GABAergic activity but only act in the early postnatal period when GABA produces excitatory signals. P2X and P2Y receptors expressed in pyramidal neurons reduce the inhibitory tone by blocking GABAA receptors. Finally, P2Y receptor activation elicits depolarization of GABAergic neurons and increases GABA release, thus favoring the emergence of gamma oscillations. The present review provides an overall picture of purinergic influence on GABAergic transmission and its consequences on neural processing, extending the discussion to receptor subtypes and their involvement in the onset of brain disorders, including epilepsy and Alzheimer's disease.
RESUMO
Huntington's (HD) and Parkinson's diseases (PD) are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms, respectively. We review here the participation of purinergic receptors through intracellular Ca2+ signaling in these neurodegenerative diseases. The adenosine A2A receptor stimulates striatopallidal GABAergic neurons, resulting in inhibitory actions on GABAergic neurons of the globus pallidus. A2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition, and A2A receptor activation results in motor inhibition. Furthermore, the A2A receptor physically and functionally interacts with glutamate receptors, mainly with the mGlu5 receptor subtype. This interaction facilitates glutamate release, resulting in NMDA glutamate receptor activation and an increase of Ca2+ influx. P2X7 receptor activation also promotes glutamate release and neuronal damage. Thus, modulation of purinergic receptor activity, such as A2A and P2X7 receptors, and subsequent aberrant Ca2+ signaling, might present interesting therapeutic potential for HD and PD.
Assuntos
Gânglios da Base/fisiopatologia , Sinalização do Cálcio , Doença de Huntington , Doença de Parkinson , Receptores Purinérgicos/metabolismo , Gânglios da Base/metabolismo , Neurônios GABAérgicos , Globo Pálido/metabolismo , Humanos , Doença de Huntington/fisiopatologia , Doença de Parkinson/fisiopatologia , Receptor A2A de Adenosina , Receptores de Dopamina D2/metabolismo , Receptores de Glutamato , Receptores Purinérgicos P2X7RESUMO
ATP (adenosine 5'-triphosphate), one of the most ancient neurotransmitters, exerts essential functions in the brain, including neurotransmission and modulation of synaptic activity. Moreover, this nucleotide has been attributed with trophic properties and experimental evidence points to the participation of ATP-activated P2X and P2Y purinergic receptors in embryonic brain development as well as in adult neurogenesis for maintenance of normal brain functions and neuroregeneration upon brain injury. We discuss here the available data on purinergic P2 receptor expression and function during brain development and in the neurogenic zones of the adult brain, as well as the insights based on the use of in vitro stem cell cultures. While several P2 receptor subtypes were shown to be expressed during in vitro and in vivo neurogenesis, specific functions have been proposed for P2Y1, P2Y2 metabotropic as well as P2X2 ionotropic receptors to promote neurogenesis. Further, the P2X7 receptor is suggested to function in the maintenance of pools of neural stem and progenitor cells through induction of proliferation or cell death, depending on the microenvironment. Pathophysiological actions have been proposed for this receptor in worsening damage in brain disease. The P2X7 receptor and possibly additional P2 receptor subtypes have been implicated in pathophysiology of neurological diseases including Parkinson's disease, Alzheimer's disease and epilepsy. New strategies in cell therapy could involve modulation of purinergic signaling, either in the achievement of more effective protocols to obtain viable and homogeneous cell populations or in the process of functional engraftment of transplanted cells into the damaged brain. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.