Modulation of calcium current in carotid body glomus cells by physiological stimuli: Effects of oxygen, carbon dioxide and nitric oxide

The carotid body (CB) is the principal peripheral chemosensory organ, located strategically at the bifurcation of the common carotid artery. It senses arterial blood levels of O₂, CO₂ and acidity and maintains homeostasis via control of breathing. Glomus cells of the CB are the putative chemoreceptors, which transduce blood-born chemical stimuli into electrical signals carried by the carotid sinus nerve, which projects to the respiratory neural network in the medulla oblongata. It is fairly well established that an increase in cytosolic Ca2+, mediated by voltage-gated Ca2+ channels, is an essential step in chemotransduction in glomus cells. In addition to the “natural stimuli” (i.e. O ₂ & CO₂), nitric oxide (NO) is another gaseous molecule that has been shown to modulate CB sensory activity. Since voltage-gated Ca 2+ channels play an important role in the chemotransduction process, I focused my studies on the modulation of Ca2+ current by O ₂, CO₂, and NO. To begin to understand the cellular mechanisms associated with the actions of these stimuli in the CB, the primary goals of this thesis were (1) to determine the effects of these stimuli on the Ca2+ current in glomus cells and (2) to elucidate the underlying cellular mechanisms. The use of dissociated glomus cells from rabbit CBs permitted direct exposure of putative chemoreceptors to these gases, and allowed Ca2+ current to be monitored using the whole-cell configuration of the patch clamp technique. Pharmacological tools were used to delineate the cellular mechanisms, which underlie O₂, CO₂, and NO modulation of Ca2+ current in glomus cells. Several types of high-voltage-activated Ca2+ channels compose the macroscopic Ca2+ current in rabbit glomus cells. Interestingly, all three gaseous stimuli affected the L-type Ca2+ current in glomus cells but by different cellular mechanisms. Low O₂ and high CO₂ augmented L-type Ca2+ current via protein kinase C and protein kinase A mechanisms, respectively. In contrast, NO inhibited the L-type Ca2+ current via nitrosylation. The L-type Ca2+ current in glomus cells has been linked to neurotransmitter release in response to natural stimuli. Taken together, these observations suggest that augmentation of L-type Ca2+ current in glomus cells by either low O₂ or high CO₂ may play a functional role by enhancing neurotransmitter release during hypoxia and hypercapnia at the CB. Furthermore, the inhibition of Ca2+ current by NO provides a plausible mechanism for efferent inhibition of CB activity.