Folia Pharmacologica Japonica

Reviews: ATP Transport System: Update

The mechanism of ATP release as an autocrine/paracrine molecule

Takeshi KATSURAGI, Keisuke MIGITA

2004 Volume 123 Issue 6 Pages 382-388
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.382

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Many studies have been performed to clarify the underlying mechanisms of the release of ATP as an autocrine / paracrine signaling molecule. So far, there is a variety of findings on the mode of release of this nucleotide. This review focused on the possible mechanisms of ATP release. The ATP binding cassette, especially CFTR (cystic fibrosis transmembrane conductance regulator), is a strong candidate for a channel or a transporter for outward movement of ATP. CFTR, which is activated via phosphorylation by protein kinase A, causes an opening of channels for Cl⁻ and ATP⁴⁻, releasing ATP. However, the possible involvement of CFTR in ATP release is still under dispute. As another candidate of the membrane machinery, the hemichannel of gap junction has been raised. Mechanical stress and photoliberation of caged InsP₃ induce the release of ATP as a paracrine through the hemichannel accompanied with the increase of [Ca²⁺]i. These events result in the Ca²⁺wave as cell-to-cell communications. In conclusion, an authoritative view of the mechanism of ATP release remains to be made clear in future studies.

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Regulation by astrocytic ATP of synaptic transmission

Schuichi KOIZUMI, Kazuhide INOUE

2004 Volume 123 Issue 6 Pages 389-396
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.389

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Originally ascribed to having only passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca²⁺ transients in astrocytes and Ca²⁺ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bi-directional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca²⁺ signaling among astrocytes, also mediates intercellular signaling between astrocytes and neurons in hippocampal cultures. Mechanical stimulation of astrocytes evoked Ca²⁺ waves mediated by the release of ATP and activation of P2 receptors. Mechanically evoked Ca²⁺ waves led to decreased excitatory glutamatergic synaptic transmission in an ATP-dependent manner. Exogenous application of ATP does not affect post-synaptic glutamatergic responses but decreased pre-synaptic exocytotic events. Finally, we show that astrocytes exhibit spontaneous Ca²⁺ oscillations mediated by extracellular ATP and that inhibition of these Ca²⁺ responses enhanced excitatory glutamatergic transmission. We therefore conclude that ATP released from astrocytes exerts tonic and activity-dependent down-regulation of synaptic transmission via pre-synaptic mechanisms.

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Extracellular ATP mediated mechano-signaling in mammary glands

Kishio FURUYA, Kumi AKITA, Masahiro SOKABE

2004 Volume 123 Issue 6 Pages 397-402
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.397

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ATP, an important and ubiquitous extracellular signaling molecule, is often released by mechanical stimuli and plays an essential role in mechano-signaling. In lactating mammary glands, secretory epithelial (SE) cells form alveoli in which milk is held, and myoepithelial (ME) cells surrounding the alveoli contract in response to oxytocin to expel milk. Previously we found that the contraction of ME cells worked as a mechanical stress to SE cells and caused ATP-release in cultured mammary epithelial cells. The released ATP activated P2Y2 in surrounding SE cells and P2Y1 in ME cells. We already reported that ATP synergistically enhanced oxytocin response in ME cells. These findings mean that ME and SE cells interact mutually via released ATP to enhance the milk ejection. Recently, we found that cell-stretch also induced Ca²⁺-increases and ATP-release. The stretching of alveoli should occur by milk filling. So, only the milk-filled alveoli (but not empty alveoli) are surrounded by ATP. The ATP lowers the threshold of the oxytocin receptors and enables the milk-filled alveoli to contract in response to oxytocin at a concentration in the blood. Slight but apparent constitutive-ATP-release was observed in non-stimulated cells and the release was enhanced in Ca²⁺-free solution. The pathway of ATP-release is not yet clear, but pharmacologically, there seems to be two or more pathways.

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ATP release pathways in vascular endothelial cells

Masahiro OIKE, Guy DROOGMANS, Yushi ITO

2004 Volume 123 Issue 6 Pages 403-411
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.403

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Vascular endothelial cells regulate vascular tonus, growth, and angiogenesis in response to mechanical stresses. ATP release is one of well-known mechanosensitive responses in endothelial cells. Released ATP induces Ca²⁺ responses and nitric oxide production in neighboring cells in an auto/paracrine manner. Mechanosensitive and agonist-induced ATP releases are also observed in other cell types, but the cellular mechanisms and pathways of ATP release are largely unknown. Reported candidates for ATP release pathways are ABC proteins including P-glycoprotein and CFTR, exocytosis of ATP-containing vesicles, and ATP-permeable anion channels. In vascular endothelium, vesicular exocytosis, volume-regulated anion channels (VRAC), and connexin hemichannels have been reported as candidates for ATP release pathways. We found that VRAC inhibitors suppressed hypotonic stress-induced ATP release in bovine aortic endothelial cells. Furthermore, extracellular ATP suppressed VRAC current in a voltage dependent manner, which could be fitted to the permeation-blocker model with a Kd(0) of 1 mM and δ value of 0.41. However, it should be noted that VRAC is probably not the only pathway for ATP release in the endothelium, because basal ATP release was not inhibited by VRAC inhibitors. Further investigations are definitely warranted to clarify the details and therapeutic significance of mechanosensitive ATP release in the endothelium.

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Technical Note

New method for quantification of cell swelling using infrared differential interference microscopy

Ryuichi NAKAJIMA, Takeshi NAKAMURA, Hiroyoshi MIYAKAWA, Yoshihisa KUDO

2004 Volume 123 Issue 6 Pages 413-419
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.413

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We have developed a novel device for the quantification of swelling of cells in acute brain slices. We can also carry out detailed real-time monitoring of hippocampal cells. The device we developed is based on an infrared differential interference contrast microscopy (IR-DIC) and a custom-made real-time computerized image analysis system for the quantification of the morphological dynamics of cells in slice preparations. We applied the coefficient of variation (CV) of light intensity in IR-DIC images to quantify the change in morphological dynamics. There were notable close relationships among the edema formations, the light transmittance, extent of changes in CV, and features of fEPSP during ischemic insult. We also applied this method for the evaluation of neuroprotective effects of mannitol. The dose-dependent improvement on the deteriorated hippocampal slices could be obtained by administration of mannitol (10, 50, and 100 mM) after 10-min ischemia. The present results indicate that CV is a reliable quantification index for edema formation of brain tissue and confirm that applying CV for the analysis in addition to the light transmittance analysis presents additional important information on brain tissue sweling.

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Drug Development Now

Current status and perspectives on the development of therapeutic agents for Alzheimer's disease

Masaaki HIROUCHI

2004 Volume 123 Issue 6 Pages 421-427
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.421

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Acetylcholinesterase inhibitors have beneficial effects to improve the cognitive impairment in patients with mild to moderate Alzheimer's disease (AD). In addition, a channel blocker of N-methyl-D-aspartate receptor, memantine hydrochloride, was approved as a therapeutic agent for patients with moderate to severe AD in both EU countries in 2002 and USA in 2003, while the clinical development is still ongoing in Japan. In contrast, the pharmacotherapy for a prime cure against AD is not available in the market, although there has been a worldwide search for novel compounds. The most plausible mechanism for the treatment of AD is the reduction of the amyloid β-peptide (Aβ) plaques, one of the pathological markers of AD, in the brain. For this purpose, the inhibitors of β-secretase and γ-secretase, which cleave amyloid precursor protein (APP) to release Aβ, has been developed to interfere with APP processing. The β-sheet breaker and metal chelators for the breakdown of aggregated Aβ have also been synthesized as well as the immunotherapeutic approach using Aβ vaccine. On the other hand, some nonsteroidal anti-inflammatory drugs, such as ibuprofen and sulindac, noncompetitively inhibited Aβ production but not Notch cleavage. The development of Aβ-lowering drugs is highly expected for the treatment of AD.

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Review on New Drug

Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole

Yasuko KOHNO, Shougo TAKEUCHI

2004 Volume 123 Issue 6 Pages 429-440
Published: 2004
Released on J-STAGE: May 25, 2004

DOIhttps://doi.org/10.1254/fpj.123.429

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Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D₂ agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D₃ subtype among the D₂ receptor subfamily members (D₂, D₃, D₄), lacking affinity with the D₁ and D₅ subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D₂ receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D₂ autoreceptor, stimulation of D₃ receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [¹²³I]2β-carboxymethoxy-3β-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.

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