title: Src family tyrosine kinases inhibit single L-type: Ca2+ channel activity in human atrial myocytes.
abstract: OBJECTIVE
  Tyrosine kinases (TKs) are important regulators of the L-type Ca(2+) channel (LTCC) current in various cell types. However, there are no data addressing the role of TKs in the control of single LTCC activity in human atrial cardiac myocytes, where changes in LTCC gating properties have been described in a number of disease states.
  
  
  RESULTS
  Single LTCC activity was recorded in isolated human atrial myocytes. The broad-spectrum TK inhibitor genistein and the Src family-selective TK inhibitor PP1 significantly enhanced single LTCC ensemble average current, availability, and open probability; the latter was due to significant increases of mean open time and mode 2 gating. Conversely, the tyrosine phosphatase inhibitor bisperoxo-phenanthroline-vanadate inhibited single LTCC activity, indicating that LTCC gating properties in human atrial myocytes are controlled by TKs and tyrosine phosphatases in a reciprocal fashion. The effects of genistein on single LTCC activity were not affected by stimulation (8Br-cAMP) or inhibition (Rp-8-CPT-cAMPS) of protein kinase A (PKA) or by inhibition of serine/threonine phosphatases types I and IIa (okadaic acid), indicating that TKs inhibit LTCC gating in human atrial myocytes independent of PKA and phosphatases types I and IIa. However, inhibition of protein kinase C (PKC) by staurosporine or bisindolylmaleimide reversed the stimulatory effects of genistein on single LTCC gating properties, indicating that PKC is required for the inhibitory effect of TKs on single LTCC activity.
  
  
  CONCLUSIONS
  Src family TKs inhibit single LTCC activity in human atrial myocytes via PKC-dependent, but PKA and phosphatase types I and IIa-independent, molecular pathways.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, Hannover 30625, Germany. schroeder.f@mh-hannover.de
authors.forename: Frank
authors.initials: F
authors.lastname: Schröder
authors.forename: Gunnar
authors.initials: G
authors.lastname: Klein
authors.forename: Tanja
authors.initials: T
authors.lastname: Frank
authors.forename: Michaela
authors.initials: M
authors.lastname: Bastein
authors.forename: Sylvio
authors.initials: S
authors.lastname: Indris
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D000368:Aged; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D019833:Genistein; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases