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The present study is focused on sediment core MD02–2521 in the Gulf of Tehuantepec (GT). This area, situated within the Oxygen Minimum Zone (OMZ), is rich in marine resources due to seasonal upwelling caused by the Tehuanos winds and a less deep thermocline representing an important economic sector of the region; however, has been the focus of a little number of studies. Benthic foraminifera (BF) are the target proxy to reconstruct bottom‑oxygen variability during the Medieval Warm Period (MWP), showing that this area was affected by cyclic variability of dissolved oxygen (DO) in 3 phases: higher, poorer, and oxygen-depleted shifting every ~90 years. The oxygen-depleted periods result in foraminiferal test dissolution, implying inevitable gaps of information. The MWP has been broadly identified as a warm anomaly in most parts of the globe and even compared with the current climate change to serve as analogous to predict future consequences. Opposing to the global warming stands, the Eastern Tropical North Pacific (ETNP) seems to have experienced a cooling trend. This study provides another proof that the MWP, besides that it is not a warm period everywhere, is also not homogeneous, so that quasi-centennial cycles may likely respond to solar activity and the dynamic interaction between decadal-to centennial phenomena such as the El Niño Southern Oscillation (ENSO), the Pacific Decadal Oscillation (PDO), and the seasonal migration of the Intertropical Convergence Zone (ITCZ).

Oceanographic dynamics in the Gulf of Tehuantepec (GT) are the direct consequence of climate variability, mainly influenced by the strong wind regime locally called “Tehuanos” and the interactions between the Intertropical Convergence Zone (ITCZ) and El Niño Southern Oscillation (ENSO). The area is characterized by intense upwelling driven by the Tehuanos within one of the largest Oxygen Minimum Zones (OMZ) in the world. Upwelling carries nutrient-rich subsurface waters to the surface and provides marine resources to the coasts conforming one of the main economic sectors in the region. In this study, sediment core MD02-2521 is used to perform the first high-resolution paleoceanographic reconstruction of the last 6 millennia in the GT. The main focus is put on the analysis of the benthic foraminifera (BF) assemblages inhabiting within the OMZ, which appear to respond to bottom oxygenation and climate variations of the last ~6000 years. The microfossil assemblages throughout the sediment core revealed, first, intervals where the lack of foraminifera provide evidence of episodes of strong deoxygenation that triggered the dissolution of calcareous foraminiferal tests, second, a long-term decline of bottom-water oxygenation in the last ~2500 years likely responding to the southward migration of the ITCZ. Last, variations in response to the transitions between cold and warm periods occurred during the last 2–2.5 millennia and cyclicities of 1470 years resembling Bond Cycles suggest a climatic connection between the Pacific and Atlantic Oceans during the late-Holocene.

This is an open access article under the terms of the Creative Commons Attribution-Non Commercial-No Derivs License., Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8BAC-EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8+ corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8+ corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people., This work was supported by grants FC-15-GRUPIN14–141 (Consejería de Economía y Empleo, Asturias, Spain), Fundación Ramón Areces, Caja Rural de Asturias, SAF2014–54518-C3-2-R, SAF2014–54518-C3-1-R, SAF2017–83674-C2-2-R, SAF2017–83674-C2-1-R, and SAF2016–77233-R (Ministerio de Economía, Industria y Competitividad, Spain and European Regional Development Funds, European Union), and “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0317).

Chemoreceptor cells of the carotid bodies (CB) are activated by hypoxia and acidosis, responding with an increase in their rate of neurotransmitter release, which in turn increases the electrical activity in the carotid sinus nerve and evokes a homeostatic hyperventilation. Studies in isolated chemoreceptor cells have shown that moderate hypoxias (≈ 46 mmHg) produces smaller depolarisations and comparable Ca2+ transients but a much higher catecholamine (CA) release response in intact CBs than intense acidic/hypercapnic stimuli (20% CO2, pH 6.6). Similarly, intense hypoxia (≈ 20 mmHg) produces smaller depolarizations and Ca2+ transients in isolated chemoreceptor cells but a higher CA release response in intact CBs than a pure depolarizing stimulus (30–35 mm external K+). Studying the mechanisms responsible for these differences we have found the following. (1) Acidic hypercapnia inhibited ICa (∼60%; whole cell) and CA release (∼45%; intact CB) elicited by ionomycin and high K+. (2) Adenylate cyclase inhibition (SQ-22536; 80 μm) inhibited the hypoxic release response (>50%) and did not affect acidic/hypercapnic release, evidencing that the high gain of hypoxia to elicit neurotransmitter release is cAMP dependent. (3) The last effect was independent of PKA activation, as three kinase inhibitors (H-89, KT 5720 and Rp-cAMP; ≥ 10 × IC50) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8-pCPT-2′-O-Me-cAMP, 100 μm) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 μm) inhibited (54%) hypoxic induced release. Our findings show for the first time that an Epac-mediated pathway mediates O2 sensing/transduction in chemoreceptor cells.

We have defined Ca2+ channel subtypes expressed in rabbit carotid body (CB) chemoreceptor cells and their participation in the stimulus-evoked catecholamine (CA) release. Ca2+ currents (I(Ca)) activated at -30 mV, peaked at +10 mV and were fully blocked by 200 microm Cd2+. L-type channels (sensitive to 2 microm nisoldipine) activated at -30 mV and carried 21 +/- 2% of total I(Ca). Non-L-type channels activated at potentials positive to -10 mV and carried: N channels (sensitive to 1 microM omega-conotoxin-GVIA) 16 +/- 1% of total I(Ca), P/Q channels (sensitive to 3 microM omega-conotoxin-MVIIC after nisoldipine plus GVIA) 23 +/- 3% of total I(Ca) and R channels (resistant to all blockers combined) 40 +/- 3% of total I(Ca). CA release induced by hypoxia, hypercapnic acidosis, dinitrophenol (DNP) and high K(+)(o) in the intact CB was inhibited by 79-98% by 200 microm Cd2+. Hypoxia, hypercapnic acidosis and DNP, depolarized chemoreceptor cells and eventually generated repetitive action potential discharge. Nisoldipine plus MVIIC nearly abolished the release of CAs induced by hypoxia and hypercapnic acidosis and reduced by 74% that induced by DNP. All these secretory responses were insensitive to GVIA. 30 and 100 mm K(+)(o) brought resting membrane potential (E(m)) of chemoreceptor cells (-48.1 +/- 1.2 mV) to -22.5 and +7.2 mV, respectively. Thirty millimolar K(+)(o)-evoked release was abolished by nisoldipine but that induced by 100 mm K(+)(o) was mediated by activation of L, N, and P/Q channels. Data show that tested stimuli depolarize rabbit CB chemoreceptor cells and elicit CA release through Ca2+ entry via voltage-activated channels. Only L and P/Q channels are tightly coupled to the secretion of CA.

Transient receptor potential melastatin 8 (TRPM8) was originally cloned from prostate tissue. Shortly thereafter, the protein was identified as a cold- and menthol-activated ion channel in peripheral sensory neurons, where it plays a critical role in cold temperature detection. In this chapter, we review our current understanding of the molecular and biophysical properties, the pharmacology, and the modulation by signaling molecules of this TRP channel. Finally, we examine the physiological role of TRPM8 and its emerging link to various human diseases, including pain, prostate cancer, dry eye disease, and metabolic disorders.

In order to better understand the post-natal increase in peripheral chemoreceptor responsiveness to hypoxia, chemoreceptors of newborn (1-2 days) and older (10-12 days, 30 days, adult) rabbits were isolated and superfused, in vitro. The free tissue catecholamine concentration was measured using carbon-fiber voltammetry and pauci-fiber nerve activity was recorded from the sinus nerve during stimulation (4 min) with graded hypoxia or increased potassium. Both the peak catecholamine and peak nerve responses to stimulation with 10% and 0% oxygen increased with age, particularly between 10 and 30 days of age. In contrast, peak nerve and peak catecholamine responses to increased potassium did not significantly change with age. For a better understanding of how responsiveness increases with age, the fast Na+ and the Ca2+ currents were measured from isolated glomus cells of newborn and older rabbits, but the magnitude of the currents when normalized to membrane area was not significantly different between ages. We conclude that: (1) rabbit chemoreceptors mature in the newborn period (10-30 days) and part of this maturation is an increase in catecholamine secretion, (2) maturation of hypoxia transduction primarily occurs in steps prior to depolarization since potassium-evoked responses were not affected, and (3) an increase in the magnitude of glomus cell fast Na+ or Ca2+ currents is not a likely mechanism for the maturational change, but changes in the oxygen sensitivity of these currents cannot be excluded.

Carotid body chemoreceptor cells in response to hypoxic and hypercapnic stimulus increase their resting rate of release of neurotransmitters and their action potential frequency in the carotid sinus sensory nerve. When chemoreceptor activity is assessed at the level of the carotid sinus nerve and on ventilation, there exists an interaction between hypoxic and hypercapnic stimulus so that the response to both stimuli combined is additive or more than additive, over a wide range of stimulation. It is not clear if this interaction occurs at chemoreceptor cell or directly acting on the sensory nerve. In the present work we demonstrate for the first time the existence of a positive interaction between hypoxic and hypercapnic-acidotic stimuli at the level of both, membrane potential depolarization and neurotransmitter release in rat and rabbit carotid body. Inhibition of adenylate cyclase (SQ-22536) abolished the positive interaction between stimuli and the Epac (exchange proteins activated by cAMP) activator 8-pCPT-2'-O-Me-cAMP reversed the effect of adenylate cyclase inhibition. These results suggest that this interaction between the two natural stimuli is mediated by cAMP via an Epac-dependent pathway, at least at the level of neurotransmitter release.

Carotid body chemoreceptor cells in response to hypoxic and hypercapnic stimulus increase their resting rate of release of neurotransmitters and their action potential frequency in the carotid sinus sensory nerve. When chemoreceptor activity is assessed at the level of the carotid sinus nerve and on ventilation, there exists an interaction between hypoxic and hypercapnic stimulus so that the response to both stimuli combined is additive or more than additive, over a wide range of stimulation. It is not clear if this interaction occurs at chemoreceptor cell or directly acting on the sensory nerve. In the present work we demonstrate for the first time the existence of a positive interaction between hypoxic and hypercapnic-acidotic stimuli at the level of both, membrane potential depolarization and neurotransmitter release in rat and rabbit carotid body. Inhibition of adenylate cyclase (SQ-22536) abolished the positive interaction between stimuli and the Epac (exchange proteins activated by cAMP) activator 8-pCPT-2'-O-Me-cAMP reversed the effect of adenylate cyclase inhibition. These results suggest that this interaction between the two natural stimuli is mediated by cAMP via an Epac-dependent pathway, at least at the level of neurotransmitter release., This work was supported by grants BFU2007-61848 (DGICYT), CIBER CB06/06/0050 (FISS-ICIII).

Chemoreceptor cells of the carotid bodies (CB) are activated by hypoxia and acidosis, responding with an increase in their rate of neurotransmitter release, which in turn increases the electrical activity in the carotid sinus nerve and evokes a homeostatic hyperventilation. Studies in isolated chemoreceptor cells have shown that moderate hypoxias ( 46 mmHg) produces smaller depolarisations and comparable Ca(2+) transients but a much higher catecholamine (CA) release response in intact CBs than intense acidic/hypercapnic stimuli (20% CO(2), pH 6.6). Similarly, intense hypoxia ( 20 mmHg) produces smaller depolarizations and Ca(2+) transients in isolated chemoreceptor cells but a higher CA release response in intact CBs than a pure depolarizing stimulus (30-35 mm external K(+)). Studying the mechanisms responsible for these differences we have found the following. (1) Acidic hypercapnia inhibited I(Ca) (60%; whole cell) and CA release (45%; intact CB) elicited by ionomycin and high K(+). (2) Adenylate cyclase inhibition (SQ-22536; 80 microm) inhibited the hypoxic release response (50%) and did not affect acidic/hypercapnic release, evidencing that the high gain of hypoxia to elicit neurotransmitter release is cAMP dependent. (3) The last effect was independent of PKA activation, as three kinase inhibitors (H-89, KT 5720 and Rp-cAMP; 10 x IC(50)) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8-pCPT-2-O-Me-cAMP, 100 microm) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 microm) inhibited (54%) hypoxic induced release. Our findings show for the first time that an Epac-mediated pathway mediates O(2) sensing/transduction in chemoreceptor cells.

Dinitrophenol (2,4 dinitrophenol; DNP) was early identified as a potent stimulant of the carotid body (CB; Shen and Hauss, 1939). DNP acts directly upon chemoreceptor cells promoting an increase in the intracellular calcium concentration and the release of catecholamine (CA); both responses are strongly dependent on the presence of Ca2+and Na+in the extracellular media (Obesoet al.1989; Rocheret al.1991; Buckler and Vaughan-Jones, 1998). The uncoupling effects of DNP have also been studied in chemoreceptor cells: DNP produces an activation of glucose consumption and a decrease in the mitochondrial membrane potential (Obesoet al.1989; Buckler and Vaughan- Jones, 1998). Mitochondrial uncouplers such as DNP, carbonyl cyanide m-chlorophenylhydrazone (CCCP) or carbonylcyanide p-(trifluoromethoxy)- phenylhydrazone (FCCP), are protonophores that produce intracellular acidification in several cell types including chemoreceptor cells (Grinstein and Rothstein, 1986; Tretteret al.1998; Buckler and Vaughan-Jones, 1998; Parket al.2002). An intracellular acidification followed by consecutive activation of Na+/H+and Na+/Ca2+exchanger was proposed by our group as the mechanism that triggers exocitosis during DNP stimulation in the adult rabbit CB (Rocheret al.1991; Gonzalezet al.1994). In rat neonatal chemoreceptor cells, however, it was found that DNP induces membrane depolarization by inhibiting a background, voltage-insensitive, K+current (Buckler and Vaughan-Jones, 1998). In addition to suppress this current, DNP also activates a yet uncharacterized inward current. In this model, an “unknown link” between DNP-induced mitochondrial depolarization and plasmalemmal K+-channels inhibition was put forward. In this paper, we have restudied the effects of DNP on rabbit chemoreceptor cells looking for the presence in this preparation of membrane depolarization. Results show that the secretion of CA induced by DNP in the rabbit CB is mostly the result of the entry of calcium to the cell via depolarization-activated calcium channels. In the discussion we reevaluate our previous data and hypothesis on the mechanism of DNP stimulation of the CB at the light of our new data. Though the nature of the membrane current targeted by DNP in rabbit CB has not been investigated, our results indicate that in adult rabbit CB chemoreceptor cells operate trough similar mechanisms than in neonatal rat CB chemoreceptor cells.