LAUSR

Blood lactate concentration under normal conditions is ~1 mM and increases during hypoxia and exercise due to elevated anaerobic metabolism. Recent studies suggest that lactate acts directly on carotid body Type 1 chemoreceptor (CB) cells and elevates cytosolic [Ca2+], which increases transmitter secretion from CB cells, carotid sinus afferent nerve activity and ventilation. The mechanism by which lactate increases [Ca2+] is still uncertain. Chang et al (2015) reported that lactate binds to Gs-coupled receptor (OlfR78 in rat/mice) whose signaling leads to a rise in [Ca2+]. Torres-Torrelo et al (2021) reported that lactate enters the cell via the monocarboxylate transporter and increases the ratio of NADH to NAD+, which opens cation channels to cause cell depolarization and Ca2+ influx. Another potential mechanism is that lactate itself inhibits K+ channels and/or activates non-selective cation channels to depolarize CB cells and increase Ca2+ influx. Here we studied the effects of lactate on ion channels, cell Em and Ca2+ oscillations in CB cells. Ion channel and Em studies: Sodium lactate (10 mM, pH 7.4) produced a mild depolarization (<10 mV) in ~30% of CB cells. In HEK cells expressing TASK-1/3, lactate (10 mM) caused mild inhibition of the whole-cell current and cell depolarization (as detected by Fluovolt fluorescence). Lactate activated a 20-pS Ca2+-sensitive monovalent cation channel (CaMCC) in ~50% of CB cells. [Ca2+] oscillations: Lactate (1-20 mM) increased the frequency of Ca2+ oscillations in CB cells (and thus averaged [Ca2+]), and this effect was blunted by removal of extracellular Ca2+, nifedipine and 2-APB. Forskolin that elevated cytosolic [cAMP] had no effect on Ca2+ oscillations, and H-89 (PKA inhibitor) did not block lactate- and hypoxia-induced increase in Ca2+ oscillations. Summary: Our studies do not support the OlfR78-Gs-cAMP signaling pathway in lactate-induced increase in Ca2+ oscillations and [Ca2+] in CB cells. Our study supports a mechanism in which lactate activates CaMCC, possibly initiated by inhibition of TASK and/or other signals, to cause cell depolarization that increases Ca2+ influx and the frequency of Ca2+ oscillations. NIH and Rosalind Franklin University of Medicine and Science This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.