Neurosteroids are steroids synthesized de novo in the brain from cholesterol in an independent manner from peripheral steroid sources. The term "neuroactive steroid" includes all steroids independent of their origin, and newly synthesized analogs of neurosteroids that modify neuronal activities. In vivo application of neuroactive steroids induces potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-aminobutyric acid type-A receptor (GABAAR). However, neuroactive steroids also act as positive or negative allosteric regulators on several ligand-gated channels including N-methyl-d-aspartate receptors (NMDARs), nicotinic acetylcholine receptors (nAChRs) and ATP-gated purinergic P2X receptors. Seven different P2X subunits (P2X1-7) can assemble to form homotrimeric or heterotrimeric ion channels permeable for monovalent cations and calcium. Among them, P2X2, P2X4, and P2X7 are the most abundant within the brain and can be regulated by neurosteroids. Transmembrane domains are necessary for neurosteroid binding, however, no generic motif of amino acids can accurately predict the neurosteroid binding site for any of the ligand-gated ion channels including P2X. Here, we will review what is currently known about the modulation of rat and human P2X by neuroactive steroids and the possible structural determinants underlying neurosteroid-induced potentiation and inhibition of the P2X2 and P2X4 receptors. This article is part of the Special Issue on "Purinergic Signaling: 50 years".

• MeSH
• adenosintrifosfát metabolismus   MeSH
• iontové kanály řízené ligandy * metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• neurosteroidy * MeSH
• purinergní receptory P2X metabolismus   MeSH
• purinergní receptory P2X2 metabolismus   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Purinergic P2X receptors (P2XR), activated by extracellular adenosine 5‘-triphosphate (ATP), represent a specific type of li- gand-gated ion channels. They form functional trimeric homomers or heteromers which are nonselectively cation-perme- able after receptor activation. P2X receptors are widely expressed in excitable and nonexcitable tissues and are involved in many physiological and pathophysiological processes such as platelet aggregation, contraction of smooth muscle, immu- ne responses, cell proliferation and apoptosis or neurotransmission. In mammals, seven P2X subunits (P2X1-P2X7) have been identified. They differ mainly in distribution, pharmacological profile and kinetics of ATP-induced responses. The sub- type P2X7 is the most specific in the P2X family and widely differs from other P2X subtypes.

• Klíčová slova
• extracelulární ATP, purinergní P2X rodina, buněčná proliferace a apoptóza,
• MeSH
• adenosintrifosfát biosyntéza   MeSH
• apoptóza fyziologie   MeSH
• extracelulární prostor MeSH
• fyziologie buňky MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• proliferace buněk MeSH
• purinergní receptory P2X - agonisté farmakokinetika   farmakologie   MeSH
• purinergní receptory P2X * analýza   biosyntéza   fyziologie   izolace a purifikace   klasifikace   metabolismus   účinky léků   MeSH
• purinergní receptory P2X1 krev   MeSH
• purinergní receptory P2X3 fyziologie   MeSH
• purinergní receptory P2X4 MeSH
• purinergní receptory P2X7 imunologie   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

The hypothalamic suprachiasmatic nuclei (SCN), the circadian master clock in mammals, releases ATP in a rhythm, but the role of extracellular ATP in the SCN is still unknown. In this study, we examined the expression and function of ATP-gated P2X receptors (P2XRs) in the SCN neurons of slices isolated from the brain of 16- to 20-day-old rats. Quantitative RT-PCR showed that the SCN contains mRNA for P2X 1-7 receptors and several G-protein-coupled P2Y receptors. Among the P2XR subunits, the P2X2 > P2X7 > P2X4 mRNAs were the most abundant. Whole-cell patch-clamp recordings from SCN neurons revealed that extracellular ATP application increased the frequency of spontaneous GABAergic IPSCs without changes in their amplitudes. The effect of ATP appears to be mediated by presynaptic P2X2Rs because ATPγS and 2MeS-ATP mimics, while the P2XR antagonist PPADS blocks, the observed enhancement of the frequency of GABA currents. There were significant differences between two SCN regions in that the effect of ATP was higher in the ventrolateral subdivision, which is densely innervated from outside the SCN. Little evidence was found for the presence of P2XR channels in somata of SCN neurons as P2X2R immunoreactivity colocalized with synapsin and ATP-induced current was observed in only 7% of cells. In fura-2 AM-loaded slices, BzATP as well as ADP stimulated intracellular Ca(2+) increase, indicating that the SCN cells express functional P2X7 and P2Y receptors. Our data suggest that ATP activates presynaptic P2X2Rs to regulate inhibitory synaptic transmission within the SCN and that this effect varies between regions.

• MeSH
• adenosintrifosfát farmakologie   MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• biofyzikální jevy účinky léků   MeSH
• blokátory sodíkových kanálů farmakologie   MeSH
• GABA farmakologie   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• messenger RNA metabolismus   MeSH
• metoda terčíkového zámku MeSH
• nervový přenos účinky léků   MeSH
• nervový útlum účinky léků   MeSH
• neurony účinky léků   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus cytologie   MeSH
• potkani Wistar MeSH
• purinergní látky farmakologie   MeSH
• purinergní receptory P2X genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• synaptické potenciály účinky léků   MeSH
• techniky in vitro MeSH
• tetrodotoxin farmakologie   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH