TRANSPORT OF HISTAMINE BY VESICULAR MONOAMINE TRANSPORTER-2

Histamine mediates signalling by a wide range of neural and non-neural cells including mast cells. Like other biogenic amines; histamine is released from specialized secretory vesicles and requires transport from the cytoplasm into these vesicles. Of the two vesicular monoamine transporters, histamine potently inhibits H-3-serotonin transport by one (VMAT2) but not the other (VMAT1). In addition, histamine-containing cells in both neural and non-neural cells express VMAT2. However, histamine lacks the hydroxyl groups generally considered necessary for recognition as a substrate by the vesicular monoamine transporters. Using a heterologous expression system, we now report that VMAT2 not only shows inhibition by histamine but also transports H-3-histamine. Interestingly, histamine differs from other monoamine transmitters and does not inhibit H-3-reserpine binding to VMAT2, indicating interaction at a distinct site. Surprisingly, reserpine inhibits histamine transport with much less potency than serotonin transport, suggesting a different transport mechanism. However, replacement of serines in the third transmembrane domain of VMAT2 that have been shown to be essential for recognition of other monoamines also eliminate H-3-histamine transport, suggesting that these serine residues may do more than simply recognize the hydroxyl groups on a monoamine substrate.