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Saccharomyces cerevisiae cells activate the Rim101 pathway to adapt to alkaline and salt stresses. On activation of this pathway, the transcription factor Rim101 undergoes proteolytic activation and regulates the expression of responsive genes. We found Rim101 to be a short‐lived protein with a half‐life of approximately 15 min. Its rapid turnover was supposedly mediated by the ubiquitin–proteasome system. Excess accumulation of the processed active Rim101 through its over‐expression conferred tolerance to both alkaline and salt stresses in yeast cells; in contrast, it had detrimental effects under cadmium stress condition. Cadmium ion inhibited proteolytic activation of Rim101, implying reciprocal interaction between the Rim101 pathway and cadmium stress. Our results showed yeast cells to be equipped with two protective systems to prevent overaccumulation of the processed active Rim101; Rim101 processing is inhibited when Rim101 level is high, and turnover of processed Rim101 is accelerated when it is abundant. Collectively, the results confirmed the flexible aspect of stress response in yeast cell; the cells not only prevent excess activation of one stress‐responsive pathway but also facilitate its attenuation to cope with other environmental stresses. [ABSTRACT FROM AUTHOR]

Summary: We investigated the potential augmenting effects of 19 clinically available antidepressants on noradrenaline (NA)‐induced contractions in guinea pig urethra smooth muscle (USM). Concentration‐response curves for NA‐induced contractions in guinea pig USM strips were obtained in the absence or presence of selected antidepressants. Desipramine, an active metabolite of imipramine, produced a contraction and potentiated NA‐induced contraction at the distal urethra without affecting the proximal urethra. Further, nortriptyline and amoxapine, tricyclic antidepressants, produced a contraction and potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected or reduced by imipramine, clomipramine, trimipramine, and amitriptyline at the proximal and distal urethra. Maprotiline, a tetracyclic antidepressant, potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected by mianserin at the proximal and distal urethra. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), potentiated NA‐induced contraction at the distal urethra, while NA‐induced contraction was unaffected by fluvoxamine, sertraline, and escitalopram at the proximal and distal urethra. Milnacipran, a serotonin‐noradrenaline reuptake inhibitor (SNRI), potentiated NA‐induced contraction at the proximal and distal urethra, whereas duloxetine potentiated it at the distal urethra. Mirtazapine slightly inhibited NA‐induced contraction at the distal urethra. Aripiprazole and sulpiride did not affect NA‐induced contractions at the proximal nor distal urethra. Trazodone inhibited NA‐induced contraction at both urethras. Desipramine, nortriptyline, amoxapine, maprotiline, paroxetine, milnacipran, and duloxetine likely induce urinary disturbance by increasing urethral resistance and augmenting NA‐induced contraction, which should be carefully considered when delivering guidance for drug administration to patients. [ABSTRACT FROM AUTHOR]

Vps34, the sole PtdIns 3-kinase in yeast, is essential for autophagy. Here, we show that the lipid-kinase activity of Vps34 is required for autophagy, implying an essential role of its product PtdIns(3) P. The protein-kinase activity of Vps15, a regulatory subunit of the PtdIns 3-kinase complex, is also required for efficient autophagy. We monitored the distribution of PtdIns(3) P in living cells using a specific indicator, the 2xFYVE domain derived from mammalian Hrs. PtdIns(3) P was abundant at endosomes and on the vacuolar membrane during logarithmic growth phase. Under starvation conditions, we observed massive transport of PtdIns(3) P into the vacuole. This accumulation was dependent on the membrane dynamics of autophagy. Notably, PtdIns(3) P was highly enriched and delivered into the vacuole as a component of autophagosome membranes but not as a cargo enclosed within them, implying direct involvement of this phosphoinositide in autophagosome formation. We also found a possible enrichment of PtdIns(3) P on the inner autophagosomal membrane compared to the outer membrane. Based on these results we discuss the function of PtdIns(3) P in autophagy. [ABSTRACT FROM AUTHOR]