Copyright © 2004, European Society of Cardiology
Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels
Department of Medical Physiology, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands
* Corresponding author. Tel.: +31 30 2538900; fax: +31 30 2539036. Email address: m.a.g.vanderheyden{at}med.uu.nl
L-type Ca2+ channels are predominantly regulated by β-adrenergic stimulation, enhancing L-type Ca2+ current by increasing the mean channel open time and/or the opening probability of functional Ca2+ channels. Stimulation of β-adrenergic receptors (ARs) results in an increased cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and consequently activation of protein kinase (PK) A and phosphorylation of L-type Ca2+ channels by this enzyme. β1-Adrenergic receptors couple exclusively to the G protein Gs, producing a widespread increase in cAMP levels in the cell, whereas β2-adrenergic receptors couple to both Gs and Gi, producing a more localized activation of L-type Ca2+ channels. Other signaling intermediates (protein kinase C, protein kinase G or protein tyrosine kinase (PTK)) either have negative effects on L-type Ca2+ current, or they interact with the stimulatory effect of the protein kinase A pathway.
KEYWORDS Adrenergic (ant)agonists; Ca-channel; Ca (cellular); G-proteins; Protein kinase A; Protein kinase C; Protein kinase G; Protein phosphatase; Protein phosphorylation; Second messengers; Tyrosine protein kinase
Abbreviations: AR, adrenergic receptor • AC, adenylate cyclase • AKAP, A kinase anchoring protein • ATP, adenosine triphosphate • Ca2+, calcium • cAMP, cyclic adenosine monophosphate • cGMP, cyclic guanosine monophosphate • DAG, 1,2-diacylglycerol • GC, guanylate cyclase • G protein, guanosine 5'-triphosphate (GTP)-binding protein • GSNO, nitrosoglutathione • ICa-L, L-type Ca2+ current • InsP3, inositol 1,4,5-triphosphate • NO, nitric oxide • PIP2, phosphatidylinositol 4,5-biphosphate • PK, protein kinase • PLC, phospholipase C • PTK, protein tyrosine kinase • Ser, serine • Thr, threonine
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