Brain synaptosomes display a diadenosine tetraphosphate (Ap4A)-mediated Ca2+ influx distinct from ATP-mediated influx

Pivorun, Edward B.; Nordone, Adrian J.

doi:10.1002/(sici)1097-4547(19960601)44:5<478::aid-jnr8>3.0.co;2-c

Cited by 22 publications

(16 citation statements)

References 54 publications

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“…However, the pharmacological properties of the different heteromeric combination of P2X subunits is not yet well understood, and the abundant presence of P2X 3 subunits has been recently described in rat midbrain synaptic terminals (Díaz-Herná ndez et al, 2001a). On the other hand, the lack of antagonism by suramin and PPADS on Ap 5 A response confirms and extends previous findings that Ap 5 Aor Ap 4 A-induced Ca 2ϩ transients were mediated by different receptors from those operated by ATP in hippocampal nerve terminals (Panchenko et al, 1996), as well as in other central nervous system areas (Pivorun and Nordone, 1996;MirasPortugal et al, 1998). Therefore, it is reasonable to think that the synaptic terminals that only responded to diadenosine polyphosphates or ATP express dinucleotide receptors or P2X receptors, respectively, but it is more difficult to know what receptor or receptors are present in the synaptosomes that responded to both agonists.…”

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confidence: 81%

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Modulation of the Rat Hippocampal Dinucleotide Receptor by Adenosine Receptor Activation

Dı́az-Hernández¹,

Pereira²,

Pintor³

et al. 2002

J Pharmacol Exp Ther

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Diadenosine pentaphosphate (Ap(5)A) and ATP stimulate an intracellular free calcium concentration ([Ca(2+)](I)) increase in rat hippocampal synaptosomes via different receptors as demonstrated by the lack of cross-desensitization between Ap(5)A and ATP responses. The ATP response was inhibited by P2 receptor antagonists and not by the dinucleotide receptor antagonist, diinosine pentaphosphate (Ip(5)I). In contrast, the Ap(5)A response was inhibited by Ip(5)I but not by P2 receptor antagonists. Studies in single hippocampal synaptic terminals showed that 31% of them responded to Ap(5)A by a [Ca(2+)](i) increase. Adenosine receptors (A(1), A(2A), and A(3)) were also present in isolated terminals as demonstrated by immunohistochemistry. The activation of A(1) or A(2A) receptors by specific agonists changed the sigmoid concentration-response curve for Ap(5)A (EC(50) = 33.5 +/- 4.5 microM) into biphasic curves. When the high-affinity adenosine receptors A(1) or A(2A) were activated, the Ap(5)A dose-response curves showed a high-affinity component with EC(50) values of 41.1 +/- 1.9 pM and 99.9 +/- 10.2 nM, respectively. The low-affinity component showed EC(50) values of 17.1 +/- 0.8 and 21.6 +/- 1.4 microM for A(1) and A(2A) receptor activation, respectively. However, the adenosine A(3) receptor activation induced a right shift of the dinucleotide concentration-response curve, showing an EC(50) value of 331.4 +/- 54.6 microM. In addition, in the presence of the A(2A) agonist, the Ap(5)A calcium influx responses were increased up to 300% of the control values. These results clearly demonstrate that the activation of presynaptic adenosine receptors is able to modulate the dinucleotide response in hippocampal nerve terminals.

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confidence: 81%

“…As the response to dinucleotides is not inhibited by ATP and analogs, a specific receptor for these compounds has been proposed. However, responses mediated through P2 receptor subtypes, which do not respond to ATP, are not excluded for dinucleotides Pivorun and Nordone, 1996).…”

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confidence: 99%

Modulation of the Rat Hippocampal Dinucleotide Receptor by Adenosine Receptor Activation

Dı́az-Hernández¹,

Pereira²,

Pintor³

et al. 2002

J Pharmacol Exp Ther

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“…In fact, the ionotropic character of the dinucleotide receptor implies Ca 2+ entry through the receptor, which depolarizes the terminal and activates Na + -and Ca 2+ -voltage-dependent channels [16,54,58,59]. It seems reasonable to propose that dinucleotides acting through this mechanism of action may modulate the release of the neurotransmitters present in the synaptic terminal.…”

Section: Overview Of Dinucleotidesmentioning

confidence: 99%

Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways

Delicado

Miras‐Portugal

Carrasquero

et al. 2006

Pflugers Arch - Eur J Physiol

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Dinucleoside polyphosphates or Ap(n)A are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Ap(4)A, Ap(5)A, and Ap(6)A are stored together with other neurotransmitters into secretory vesicles and are co-released to the extracellular medium upon stimulation. These compounds can interact extracellularly with some ATP receptors, both metabotropic (P2Y) and ionotropic (P2X). However, specific receptors for these substances, other than ATP receptors, have been described in presynaptic terminals form rat midbrain. These specific dinucleotide receptors are of ionotropic nature and their activation induces calcium entry into the terminals and the subsequent neurotransmitter release. Calcium signals that cannot be attributable to the interaction of Ap(n)A with ATP receptors have also been described in cerebellar synaptosomes and granule cell neurons in culture, where Ap(5)A induces CaMKII activation. In addition, cerebellar astrocytes express a specific Ap(5)A receptor coupled to ERK activation. Ap(5)A engaged to MAPK cascade by a mechanism that was insensitive to pertussis toxin and required the involvement of src and ras proteins. Diadenosine polyphosphates, acting on their specific receptors and/or ATP receptors, can also interact with other neurotransmitter systems. This broad range of actions and interactions open a promising perspective for some relevant physiological roles for the dinucleotides. However, the physiological significance of these compounds in the CNS is still to be determined.

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“…Diadenosine tetraphosphate and diadenosine pentaphosphate (Ap 5A) appeared after stimulation at nanomolar concentrations, thus allowing their interaction with plasma membrane nucleotide receptors (P2 purinoceptors) (Hoyle, 1990;Abbracchio and Burnstock, 1995;Boarder et al, 1995; Miras-Portugal, 1 995a; . Recently, a new purinergic receptor sensitive to adenine dinucleotides and insensitive to ATP has been characterized (Pintor and Miras-Portugal, 1995b;Schubert et al, 1995;Pivorun and Nordone, 1996). This receptor, termed P4 purinoceptor or dinucleotide receptor, induces a Ca 2~influx in midbrain synaptic terminals and in CA3 hippocampal neurons (Pintor and Miras-Portugal, 1995b;Panchenko et al, 1996).…”

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confidence: 99%

Dinucleotide Receptor Modulation by Protein Kinases (Protein Kinases A and C) and Protein Phosphatases in Rat Brain Synaptic Terminals

Pintor

Gualix²,

Miras‐Portugal³

1997

Journal of Neurochemistry

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The diadenosine polyphosphates, diadenosine tetraphosphate and diadenosine pentaphosphate (Ap 5A), can activate an ionotropic dinucleotide receptor that induces Ca 2~transients into synaptosomes prepared from rat brain. This receptor, also termed the P 4 purinoceptor, is sensitive only to adenine dinucleotides and is insensitive to ATP. Studies on the modulatory role of protein kinase A (PKA), protein kinase C (PKC), and protein phosphatases on the response of diadenosine polyphosphate receptors were performed by measuring the changes in the intracellular Ca 2~levels with fura-2. Activation and inhibition of PKA were carried out by means of forskolin and the PKA inhibitory peptide(PKA-IP), respectively. The Ap 5A response was inhibited by forksolin to 35% of control values, but PKA-IP induced an increase of 37%. The effect of PKC activation was similar to that observed for PKA. PKC stimulation with phorbol 12,13dibutyrate produced an inhibition of 67%, whereas the PKC inhibitors staurosporine and PKC inhibitory peptide enhanced the responses elicited by Ap5A to 40% in both cases. Protein phosphatase inhibitors diminished the responses elicited by Ap5A to 17% in the case of okadaic acid, to 50% for microcystin, and to 45% in the case of cyclosporin A. Thus, the activity of dinucleotide receptors in rat brain synaptosomes appears to be modulated by phosphorylation/dephosphorylation. These processes could be of physiological significance in the control of transmitter release from neurons that are postsynaptic to nerves that release diadenosine polyphosphates.

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Brain synaptosomes display a diadenosine tetraphosphate (Ap4A)-mediated Ca2+ influx distinct from ATP-mediated influx

Cited by 22 publications

References 54 publications

Modulation of the Rat Hippocampal Dinucleotide Receptor by Adenosine Receptor Activation

Modulation of the Rat Hippocampal Dinucleotide Receptor by Adenosine Receptor Activation

Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways

Dinucleotide Receptor Modulation by Protein Kinases (Protein Kinases A and C) and Protein Phosphatases in Rat Brain Synaptic Terminals

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