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A novel nonopioid action of enkephalins: competitive inhibition of the mammalian brain high affinity L-proline transporter

RT Fremeau , M Velaz-Faircloth, JW Miller, VA Henzi, SM Cohen, JV Nadler, S Shafqat, RD Blakely and B Domin

Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA. rtf@galactose.mc.duke.edu

The high affinity L-proline transporter (PROT) is a member of the family of Na+ (and Cl-)-dependent plasma membrane transport proteins that comprises transporters for several neurotransmitters, osmolytes, and metabolites. The brain-specific expression of PROT in a subset of putative glutamatergic pathways implies a specialized function for this novel transporter and its presumed natural substrate L-proline in excitatory synaptic transmission. However, definitive studies of the physiological role(s) of high affinity L-proline uptake have been precluded by the lack of specific uptake inhibitors. Here, we report that Leu- and Met-enkephalin and their des-tyrosyl derivatives potently and selectively inhibited high affinity L-proline uptake in rat hippocampal synaptosomes and in PROT-transfected HeLa cells. High concentrations of the opiate receptor antagonist naltrexone did not block the inhibitory actions of these peptides, arguing against an involvement of opioid receptors. Des-tyrosyl-Leu-enkephalin elevated the apparent K(m) of L-proline transport in transfected HeLa cells without altering the V(max). PROT-transfected HeLa cells did not accumulate [3H]Leu-enkephalin above background levels, demonstrating that enkephalins are not substrates for PROT. These findings indicate that enkephalins competitively inhibit mammalian brain PROT through a direct interaction with the transporter protein at or near the L- proline binding site. The high potency and specificity of des-tyrosyl- Leu-enkephalin make this compound a useful tool for elucidating the structure-function properties and physiological role(s) of PROT.

Volume 49, Issue 6, pp. 1033-1041, 06/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics