Since stimulation-induced uptake of the endocytosis marker FM1-43

Since stimulation-induced uptake of the endocytosis marker FM1-43 was inhibited by blocking vATPase (folimycin, Figure 5), it is likely that the cytosolic alkalinization generated when this pump is incorporated into the plasma membrane facilitates vesicle recycling under physiological conditions. Consistent with this hypothesis, in hippocampal synapses, folimycin caused rapid use-dependent depression of evoked transmitter release selleckchem (Ertunc et al., 2007), which could be mimicked by inhibition of endocytosis by dynasore in the same system (Chung et al., 2010). Reduced endocytosis may impair vesicular release by inhibiting

vesicle reuse, or by preventing docking of new vesicles at exocytotic sites (Kawasaki et al., 2000 and Hosoi et al.,

2009). Possible mechanisms underlying the favorable effect of alkalinization include the pH sensitivity of internalization of clathrin-coated pits from MDV3100 ic50 the plasma membrane and of dynamin-adaptin binding; both of these processes are inhibited by cytosolic acidification (Sandvig et al., 1987, Davoust et al., 1987, Heuser, 1989 and Wang et al., 1995). Also, endocytosis in yeast cells is markedly slowed by pharmacological or genetic block of vATPase (folimycin, null vATPase mutants; Perzov et al., 2002). Incorporation of other vesicular proteins may also promote endocytosis. For example, in Drosophila motor terminals, activity-induced incorporation of a vesicular protein (flower) into the plasma membrane maintains cytosolic [Ca2+] at levels that support endocytosis ( Yao et al., 2009). In snake and mouse motor terminals there is evidence that at some stimulation frequencies, preferred sites of endocytosis colocalize with preferred sites of exocytosis (Teng et al., 1999 and Gaffield et al., 2009). Our finding that multiple terminal subregions (∼2 μm2) experience stimulation-induced alkalinizations much larger than average (Figure S3) provides a possible explanation for this colocalization: local

alkaline domains, created by exocytotic insertion of vATPase, would favor endocytosis at or near sites of prior exocytosis. Localized insertion of vATPase due to vesicular exocytosis might also provide a possible STK38 explanation for the observation that the pH is more alkaline (by 0.2–0.3 pH units) in neuronal growth cones than in the soma (Dickens et al., 1989). Another beneficial effect of the stimulation-induced cytosolic alkalinization may be maintaining the presynaptic Ca2+ currents. Work in a variety of neurons indicates that cytosolic acidification depresses and/or alkalinization enhances VDCCs (isolated hippocampal CA1 neurons, Tombaugh and Somjen, 1997 and Tombaugh, 1998; N-type Ca2+ currents in chick sensory neurons, Kiss and Korn, 1999).

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