Cav3.1 (alpha1G) T-type Ca2+ channels mediate vaso-occlusion of sickled erythrocytes in lung microcirculation.
In the present study, we demonstrate that lung microvascular endothelial cells express a Cav3.1 (alpha1G) T-type voltage-gated Ca2+ channel, whereas lung macrovascular endothelial cells do not express voltage-gated Ca2+ channels. Voltage-dependent activation indicates that the Cav3.1 T-type Ca2+ current is shifted to a positive potential, at which maximum current activation is -10 mV; voltage-dependent conductance and inactivation properties suggest a "window current" in the range of -60 to -30 mV. Thrombin-induced transitions in membrane potential activate the Cav3.1 channel, resulting in a physiologically relevant rise in cytosolic Ca2+. Furthermore, activation of the Cav3.1 channel induces a procoagulant endothelial phenotype; eg, channel inhibition attenuates increased retention of sickled erythrocytes in the inflamed pulmonary circulation. We conclude that activation of the Cav3.1 channels selectively induces phenotypic changes in microvascular endothelial cells that mediate vaso-occlusion by sickled erythrocytes in the inflamed lung microcirculation.
Wu
Songwei
S
Department of Pharmacology, University of South Alabama College of Medicine, Mobile, Ala 36688, USA. swu@jaguar1.usouthal.edu
Haynes
Johnson
J
Taylor
James T
JT
Obiako
Boniface O
BO
Stubbs
James R
JR
Li
Ming
M
Stevens
Troy
T
D000595:Amino Acid Sequence; D000755:Anemia, Sickle Cell / Q000097:blood / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004913:Erythrocytes, Abnormal / Q000473:pathology*; D005444:Flunarizine / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008564:Membrane Potentials / Q000187:drug effects; D020748:Mibefradil / Q000494:pharmacology; D008833:Microcirculation / Q000503:physiopathology; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012604:Scorpion Venoms / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D009498:Neurotoxins; D012604:Scorpion Venoms; C118444:kurtoxin; D010868:Pimozide; D020748:Mibefradil; D012313:RNA; D009532:Nickel; D005444:Flunarizine; D002118:Calcium