Norepinephrine transporters have channel modes of conduction - PubMed (original) (raw)

Norepinephrine transporters have channel modes of conduction

A Galli et al. Proc Natl Acad Sci U S A. 1996.

Abstract

Neurotransmitter transporters couple to existing ion gradients to achieve reuptake of transmitter into presynaptic terminals. For coupled cotransport, substrates and ions cross the membrane in fixed stoichiometry. This is in contrast to ion channels, which carry an arbitrary number of ions depending on the channel open time. Members of the gamma-aminobutyric acid transporter gene family presumably function with fixed stoichiometry in which a set number of ions cotransport with one transmitter 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 events are stimulated by NE and by guanethidine, an hNET substrate, and they are blocked by cocaine and the antidepressant desipramine. Voltage-clamp data combined with NE uptake data from these same cells indicate that hNETs have two functional modes of conduction: a classical transporter 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 same 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 occurs with low probability. This is because each C-mode opening transports hundreds of charges per event. The existence of a channel mode of conduction in a previously established fixed-stoichiometry transporter suggests the appearance of an aqueous pore through the transporter protein during the transport cycle and may have significance for transporter regulation.

PubMed Disclaimer

Cited by

Differential regulation of mammalian brain-specific proline transporter by calcium and calcium-dependent protein kinases.
Jayanthi LD, Wilson JJ, Montalvo J, DeFelice LJ. Jayanthi LD, et al. Br J Pharmacol. 2000 Feb;129(3):465-70. doi: 10.1038/sj.bjp.0703071. Br J Pharmacol. 2000. PMID: 10711344 Free PMC article.
GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine.
Horton DB, Nickell JR, Zheng G, Crooks PA, Dwoskin LP. Horton DB, et al. J Neurochem. 2013 Oct;127(2):177-86. doi: 10.1111/jnc.12371. Epub 2013 Aug 19. J Neurochem. 2013. PMID: 23875622 Free PMC article.
Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
Bowton E, Saunders C, Erreger K, Sakrikar D, Matthies HJ, Sen N, Jessen T, Colbran RJ, Caron MG, Javitch JA, Blakely RD, Galli A. Bowton E, et al. J Neurosci. 2010 Apr 28;30(17):6048-57. doi: 10.1523/JNEUROSCI.5094-09.2010. J Neurosci. 2010. PMID: 20427663 Free PMC article.
Electrical and Mechanical Strategies to Enable Cardiac Repair and Regeneration.
Cao H, Kang BJ, Lee CA, Shung KK, Hsiai TK. Cao H, et al. IEEE Rev Biomed Eng. 2015;8:114-24. doi: 10.1109/RBME.2015.2431681. Epub 2015 May 11. IEEE Rev Biomed Eng. 2015. PMID: 25974948 Free PMC article. Review.
Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channel.
Wadiche JI, Kavanaugh MP. Wadiche JI, et al. J Neurosci. 1998 Oct 1;18(19):7650-61. doi: 10.1523/JNEUROSCI.18-19-07650.1998. J Neurosci. 1998. PMID: 9742136 Free PMC article.

References

1. J Neurosci. 1996 Jan 15;16(2):436-47 - PubMed
1. J Exp Biol. 1995 Oct;198(Pt 10):2197-212 - PubMed
1. J Physiol. 1996 Feb 1;490 ( Pt 3):691-702 - PubMed
1. Biophys J. 1996 Feb;70(2):733-42 - PubMed
1. Science. 1961 Feb 10;133(3450):383-4 - PubMed

Norepinephrine transporters have channel modes of conduction - PubMed (original) (raw)