Proton pumps and chemiosmotic coupling as a generalized mechanism for neurotransmitter and hormone transport

Neuroendocrine secretory vesicles contain within their membranes a highly specialized H1-translocating ATPase responsible for the generation and maintenance of an electrochemical proton gradient, delta pH inside acidic, and delta psi inside positive. Coupled with a high internal buffering capacity and extremely low permeability of the membrane to protons, this proton pump can generate and maintain an intravesicular pH of 5.5, independent of the external pH, and transmembrane electrical potential of 60 mV. The chemiosmotic gradient has important implications for several functions of the secretory vesicles: (1) maintaining oxidizable substances (such as biogenic amines) in the unoxidized form; (2) stimulating (or inhibiting) peptide processing enzymes; (3) permitting precipitation of intravesicular protein complexes, thereby increasing the amount that can be stored within the vesicle; and (4) serving as the driving force for the uptake of certain hormones and neurotransmitters such as acetylcholine, biogenic amines, and ATP. By using the putative biogenic amine transporter as an example, it can be demonstrated that based purely upon the existence of a transporter in equilibrium with the electrochemical proton gradients, an amine concentration approaching 135,000 to 1 can be achieved. The bioenergetics of amine transport do not predict the molecular mechanism of amine translocation. By using kinetic analyses of amine accumulation under a variety of situations, however, initial information concerning the salient aspects of amine transport is being obtained.