Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the a and g subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange was required for terrestrial survival.

Hypercapnia Regulates Gene Expression and Tissue Function

Carbon dioxide (CO2) is produced in eukaryotic cells primarily during aerobic respiration, resulting in higher CO2 levels in mammalian tissues than those in the atmosphere. CO2 like other gaseous molecules such as oxygen and nitric oxide, is sensed by cells and contributes to cellular and organismal physiology. In humans, elevation of CO2 levels in tissues and the bloodstream (hypercapnia) occurs during impaired alveolar gas exchange in patients with severe acute and chronic lung diseases. Advances in understanding of the biology of high CO2 effects reveal that the changes in CO2 levels are sensed in cells resulting in specific tissue responses. There is accumulating evidence on the transcriptional response to elevated CO2 levels that alters gene expression and activates signaling pathways with consequences for cellular and tissue functions. The nature of hypercapnia-responsive transcriptional regulation is an emerging area of research, as the responses to hypercapnia in different cell types, tissues, and species are not fully understood. Here, we review the current understanding of hypercapnia effects on gene transcription and consequent cellular and tissue functions.

Activation by Cleavage of the Epithelial Na+ Channel α and γ Subunits Independently Coevolved with the Vertebrate Terrestrial Migration

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the αand γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange was required for terrestrial survival.

Mouth Pain in Horses: Physiological Foundations, Behavioural Indices, Welfare Implications, and a Suggested Solution

A proposition addressed here is that, although bitted horses are viewed by many equestrians as being largely free of bit-related mouth pain, it seems likely that most behavioural signs of such pain are simply not recognised. Background information is provided on the following: the major features of pain generation and experience; cerebrocortical involvement in the conscious experience of pain by mammals; the numerous other subjective experiences mammals can have; adjunct physiological responses to pain; some general feature of behavioural responses to pain; and the neural bases of sensations generated within the mouth. Mouth pain in horses is then discussed. The areas considered exclude dental disease, but they include the stimulation of pain receptors by bits in the interdental space, the tongue, the commissures of the mouth, and the buccal mucosa. Compression, laceration, inflammation, impeded tissue blood flow, and tissue stretching are evaluated as noxious stimuli. The high pain sensitivity of the interdental space is described, as are likely increases in pain sensitivity due to repeated bit contact with bruises, cuts, tears, and/or ulcers wherever they are located in the mouth. Behavioural indices of mouth pain are then identified by contrasting the behaviours of horses when wearing bitted bridles, when changed from bitted to bit-free bridles, and when free-roaming unbitted in the wild. Observed indicative behaviours involve mouth movements, head-neck position, and facial expression (“pain face”), as well as characteristic body movements and gait. The welfare impacts of bit-related pain include the noxiousness of the pain itself as well as likely anxiety when anticipating the pain and fear whilst experiencing it, especially if the pain is severe. In addition, particular mouth behaviours impede airflow within the air passages of the upper respiratory system, effects that, in their turn, adversely affect the air passages in the lungs. Here, they increase airflow resistance and decrease alveolar gas exchange, giving rise to suffocating experiences of breathlessness. In addition, breathlessness is a likely consequence of the low jowl angles commonly maintained during dressage. If severe, as with pain, the prospect of breathlessness is likely to give rise to anxiety and the direct experience of breathlessness to fear. The related components of welfare compromise therefore likely involve pain, breathlessness, anxiety, and fear. Finally, a 12-point strategy is proposed to give greater impetus to a wider adoption of bit-free bridles in order to avoid bit-induced mouth pain.