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Differential regulation of mammalian brain‐specific proline transporter by calcium and calcium‐dependent protein kinases
Author(s) -
Jayanthi Lankupalle D,
Wilson Jennifer J,
Montalvo Jocelyn,
DeFelice Louis J
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703071
Subject(s) - thapsigargin , protein kinase c , camk , calphostin c , activator (genetics) , microbiology and biotechnology , kinase , calmodulin , protein kinase a , calcium , biology , phorbol , chemistry , medicine , endocrinology , biochemistry , receptor , intracellular , autophosphorylation
This study examined the role of [Ca 2+ ] I and Ca 2+ ‐dependent kinases in the modulation of high‐affinity, mammalian brain‐specific L ‐proline transporter (PROT). β‐PMA (phorbol 12‐myristate 13‐acetate), an activator of protein kinase C (PKC), inhibits PRO uptake, and bisindolylmalemide I (BIM), a potent PKC inhibitor, prevents β‐PMA inhibition. Down‐regulation of PKC by chronic treatment with β‐PMA enhances PROT function indicating PROT regulation by tonic activity of PKC. Thapsigargin, which increases [Ca 2+ ] I levels by inhibiting Ca 2+ ‐ATPase, inhibits PROT and exhibits additive inhibition when co‐treated with β‐PMA. KN‐62, a Ca 2+ /calmodulin‐dependent kinase II (CaMK II) inhibitor, but not BIM (a PKC inhibitor) prevents the inhibition by thapsigargin. These data suggest that PKC and CaMK II modulate PROT and that thapsigargin mediates its effect via CaMK II. Thapsigargin raises [Ca 2+ ] I and increases PRO‐induced current on a second time scale, whereas the inhibitory effect of thapsigargin occurs only after 10 min of treatment. These data suggest that Ca 2+ differentially regulate PROT: Ca 2+ initially enhances PRO transport but eventually inhibits transport function through CaMK II pathway. Ca 2+ ‐induced stimulation exemplifies the acute regulation of a neurotransmitter transporter, which may play a critical role in the profile of neurotransmitters during synaptic transmissionBritish Journal of Pharmacology (2000) 129 , 465–470; doi: 10.1038/sj.bjp.0703071