-Conopeptide MrIA (-MrIA) is a 13-residue peptide contained in the venom of the predatory marine snail Conus marmoreus that has been found to inhibit the norepinephrine transporter (NET). We investigated whether -MrIA targeted the other members of the monoamine transporter family and found no effect of the peptide (100 M) on the activity of the dopamine transporter and the serotonin transporter, indicating a high specificity of action. The binding of the NET inhibitors, [ Because of its poor lipid solubility and degree of ionization at physiological pH, norepinephrine crosses cell membranes poorly by diffusion (1) and so relies on the operation of the norepinephrine transporter (NET) 1 for uptake into cells. Clearance by this integral membrane protein constitutes the major mechanism for the termination of action of this neurotransmitter at noradrenergic synapses (2), and disturbances in the functioning of the NET are associated with pathological states including depression (3), congestive heart failure (4), and orthostatic intolerance, and tachycardia (5). Known inhibitors of the NET include antidepressants (e.g. desipramine and nisoxetine), the appetite suppressant mazindol, and the abused drug cocaine (for review, see Ref. 6). The NET, together with the dopamine transporter (DAT) and the serotonin transporter (SERT), forms a family of Na ϩ -and Cl