NOREPINEPHRINE TRANSPORTERS HAVE CHANNEL MODES OF CONDUCTION

Neurotransmitter transporters couple to existing ion gradients to achi eve reuptake of transmitter into presynaptic terminals. For coupled co transport, substrates and ions cross the membrane in fixed stoichiomet ry. This is in contrast to ion channels, which carry an arbitrary numb er of ions depending on the channel open time. Members of the gamma-am inobutyric acid transporter gene family presumably function with fixed stoichiometry in which a set number of ions cotransport with one tran smitter molecule. Here we report channel-like events from a presumably fixed stoichiometry [norepinephrine (NE)(+), Na+, and Cl-], human NE (hNET) in the gamma-aminobutyric acid transporter gene family. These e vents are stimulated by NE and by guanethidine, an hNET substrate, and they are blocked by cocaine and the antidepressant desipramine. Volta ge-clamp data combined with NE uptake data from these same cells indic ate that hNETs have two functional modes of conduction: a classical tr ansporter mode (T-mode) and a novel channel mode (C-mode). Both T-mode and C-mode are gated by the same substrates and antagonized by the sa me blockers. T-mode is putatively electrogenic because the transmitter and cotransported ions sum to one net charge. However, C-mode carries virtually all of the transmitter-induced current, even though it occu rs with low probability. This is because each C-mode opening transport s hundreds of charges per event. The existence of a channel mode of co nduction in a previously established fixed-stoichiometry transporter s uggests the appearance of an aqueous pore through the transporter prot ein during the transport cycle and may have significance for transport er regulation.