CaV3.2 T-type Ca²⁺ channels in H₂S-mediated hypoxic response of the carotid body.
Arterial blood O2 levels are detected by specialized sensory organs called carotid bodies. Voltage-gated Ca(2+) channels (VGCCs) are important for carotid body O2 sensing. Given that T-type VGCCs contribute to nociceptive sensation, we hypothesized that they participate in carotid body O2 sensing. The rat carotid body expresses high levels of mRNA encoding the α1H-subunit, and α1H protein is localized to glomus cells, the primary O2-sensing cells in the chemoreceptor tissue, suggesting that CaV3.2 is the major T-type VGCC isoform expressed in the carotid body. Mibefradil and TTA-A2, selective blockers of the T-type VGCC, markedly attenuated elevation of hypoxia-evoked intracellular Ca(2+) concentration, secretion of catecholamines from glomus cells, and sensory excitation of the rat carotid body. Similar results were obtained in the carotid body and glomus cells from CaV3.2 knockout (Cacna1h(-/-)) mice. Since cystathionine-γ-lyase (CSE)-derived H2S is a critical mediator of the carotid body response to hypoxia, the role of T-type VGCCs in H2S-mediated O2 sensing was examined. Like hypoxia, NaHS, a H2S donor, increased intracellular Ca(2+) concentration and augmented carotid body sensory nerve activity in wild-type mice, and these effects were markedly attenuated in Cacna1h(-/-) mice. In wild-type mice, TTA-A2 markedly attenuated glomus cell and carotid body sensory nerve responses to hypoxia, and these effects were absent in CSE knockout mice. These results demonstrate that CaV3.2 T-type VGCCs contribute to the H2S-mediated carotid body response to hypoxia.
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Vladislav V
VV
Makarenko
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Ying-Jie
YJ
Peng
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Guoxiang
G
Yuan
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Aaron P
AP
Fox
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Ganesh K
GK
Kumar
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois.
Jayasri
J
Nanduri
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, Illinois nanduri@uchicago.edu.
Nanduri R
NR
Prabhakar
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides
D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D002395:Catecholamines; D013440:Sulfides; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D010100:Oxygen; D002118:Calcium; D006862:Hydrogen Sulfide
O2 sensing; T-type calcium channel; carotid body; mibefradil; voltage-gated calcium channels