ABSCISIC ACID: A UNIVERSAL SIGNALING FACTOR?

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In 1986, two papers appeared that raised the possibility that abscisic acid (ABA) might be a universal signaling factor. In the first, Le Page-Degivry et al. (1986) established the presence of ABA in the brains of rats and pigs. In the second, Huddart et al. (1986) proposed, based on experiments with various smooth muscle preparations and a cyanobacterium that ABA may serve as a universal Ca²⁺ agonist across taxonomic kingdoms. This month's News from the Archives reviews how the concept of ABA being a universal signaling factor has fared in the ensuing years.

	ABA Present in Brains

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Le Page-Degivry et al. (1986) identified (+)-cis-ABA in the brains of pigs and rats by means of a very specific radioimmunoassay. The authors found that the final product of purification from mammalian brain had the same properties as authentic ABA: It cross-reacted in the ABA radioimmunoassay and had the same retention properties and the same gas chromatography/mass spectrometry characteristics. Moreover, like (+)-cis-ABA itself, the brain factor decreased the stomatal apertures of abaxial epidermis strips of Setcreasea purpurea. They also found evidence for the presence of ABA conjugates (esters and glucosides) in brain similar to those found in plants. Of course, the presence of ABA in the brain could be interpreted to be a consequence of a diet containing ABA. This would not, however, account for the especially high levels of ABA found in the pig brain compared with other organs (heart, liver, kidneys, and lungs). Moreover, rats fed a synthetic diet poor in ABA were actually found to have higher levels of brain ABA than rats fed a normal diet. While their discovery of ABA in mammalian brains was intriguing, the authors did not speculate as to a possible function of ABA in brain tissue. Nor has much been published about a possible role for ABA in brain function in the ensuing years.

The one exception is a report by Pidoplichko and Reymann (1994), who provided evidence that pre-exposure to trans,trans-ABA, which is not the ABA isomer used by plants, induced a marked increase of the fast component of N-methyl-D-Asp (NMDA)-gated currents in isolated rat hippocampal neurons. Since the NMDA receptor is a subtype of the ionotropic Glu receptor (iGluR) gene family, and members of this family have recently been discovered in Arabidopsis (Chiu et al., 1999), perhaps a closer examination of the effects of ABA and its various isomers on plant iGluR function might be worthwhile.

In short, the role, if any, of ABA in brain function remains as mysterious as the day its presence in brains was first reported.

	ABA: A Ca2+ Agonist in Smooth Muscle?

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Huddart et al. (1986) presented evidence concerning the effects of ABA on several mammalian smooth muscle preparations and on a cyanobacterium. Studies on smooth muscles from the vas deferens and bladder of rat showed that 10⁶ M ABA enhanced field stimulation responses by 25%. This effect was inhibited by the Ca²⁺ channel blocker nifedipine. In K⁺-depolarized bladder smooth muscle in which the fast Ca²⁺ channels were inactivated, 10⁶ M ABA augmented contraction tension and enhanced the slow tonic phase of the response, which is known to be dependent on the activity of slow Ca²⁺ channels. Even more impressive effects were found with rat ileal smooth muscle. ABA at concentrations of 10⁹ to 10⁸ M caused enhancement of K⁺ contracture tension by up to 400%. This response is strongly dependent upon extracellular Ca²⁺. Preliminary data indicated that ABA enhances the influx of Ca²⁺ occurring after K⁺ depolarization by about 60%. Thus, the results attained by Huddart et al. (1986) using all three smooth muscle preparations were consistent with the idea that ABA might act as a plasma membrane Ca²⁺ channel agonist.

The first follow-up study from Huddart's laboratory seemed to confirm the effects of ABA on smooth muscle function. Langton and Huddart (1988) reported that ABA was particularly effective in potentiating the tonic component of K⁺-induced contractures in rat smooth muscle vas deferens, particularly in muscles isolated from the epididymis. Lynch (1991), however, found that the ABA analog SD217595 at 10⁶ M caused an inhibition of K⁺-induced phasic and tonic contractions of rat bladder detrusor smooth muscle strips. The inhibition of contraction induced by SD217595 was in stark contrast to the potentiation of smooth muscle contraction reported previously by Huddart's group with the parent molecule ABA. Later, Masters et al. (1994), also of Huddart's laboratory, published a near retraction of Langton and Huddart's (1988) results, and concluded that ABA was without significant Ca²⁺-modulatory activity in their rat vas deferens smooth muscle preparation. Like Lynch (1991), however, they found that the ABA analog SD217595 possessed strong Ca²⁺ entry blocking ability.

In short, data concerning the positive effects of ABA on smooth muscle preparations seem conflicted at best.

	ABA: A Ca2+ Agonist in Cyanobacteria?

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In the case of cyanobacteria, Huddart et al. (1986) reported that 10⁷ M ABA caused a significant ratio in the heterocyst to vegetative cell ratio of Nostoc 6720. Preliminary data also indicated that ABA led to an increase in Ca²⁺ uptake (see also Pandey et al., 1996). The Ca²⁺ ionophore A23187, like ABA, also caused an increase in heterocyst frequency. Subsequent studies revealed that ABA and A23187 also led to an increase in nitrogenase activity (Smith et al., 1987; see also Marsálek and Simek, 1992). The physiological significance of the above studies is heightened by the discovery that cyanobacteria produce ABA (Zahardnickova et al., 1991). Current evidence, therefore, is consistent with the idea that ABA may be an important physiological factor in cyanobacteria.

	ABA and Temperature Signaling in Sponges

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The idea that ABA may also serve a signaling role in animal cells received a big boost from the recent findings of Zocchi et al. (2001). These authors demonstrated that ABA stimulates an ADP-ribosyl cyclase activity in sponges. This enzyme converts NAD⁺ into cADP-Rib, a potent and universal intracellular Ca²⁺ mobilizer that has also been implicated in ABA signal transduction in plants (Wu et al., 1997). Pharmacological evidence indicated that ADP-ribosyl cyclase in Axinella polypoides was activated by temperature increases by means of an ABA-induced, protein kinase A-dependent mechanism. Sponges (phylum Porifera) are among the oldest multicellular animals, their evolution dating back to 600 million years ago. These results suggest an ancient evolutionary origin of this stress-signaling cascade.