The inevitability of ATP as a transmitter in the carotid body

Abstract

Atmospheric oxygen concentrations rose markedly at several points in evolutionary history. Each of these increases was followed by an evolutionary leap in organismal complexity, and thus the cellular adaptions we see today have been shaped by the levels of oxygen within our atmosphere. In eukaryotic cells, oxygen is essential for the production of adenosine 5′-triphosphate (ATP) which is the ‘Universal Energy Currency’ of life. Aerobic organisms survived by evolving precise mechanisms for converting oxygen within the environment into energy. Higher mammals developed specialised organs for detecting and responding to changes in oxygen content to maintain gaseous homeostasis for survival. Hypoxia is sensed by the carotid bodies, the primary chemoreceptor organs which utilise multiple neurotransmitters one of which is ATP to evoke compensatory reflexes. Yet, a paradox is presented in oxygen sensing cells of the carotid body when during periods of low oxygen, ATP is seemingly released in abundance to transmit this signal although the synthesis of ATP is theoretically halted because of its dependence on oxygen. We propose potential mechanisms to maintain ATP production in hypoxia and summarise recent data revealing elevated sensitivity of purinergic signalling within the carotid body during conditions of sympathetic overactivity and hypertension. We propose the carotid body is hypoxic in numerous chronic cardiovascular and respiratory diseases and highlight the therapeutic potential for modulating purinergic transmission.

Introduction

The emergence of complex life and the evolutionary adaptations we see on Earth today were made possible and indeed, were shaped by harnessing rising oxygen (O₂) levels in the atmosphere. Modern eukaryotes are critically dependent on the availability and utilisation of O₂ for survival, and over time terrestrial mammals have evolved specialised organs capable of detecting changes in O₂. In humans, the carotid bodies (CBs) are the primary chemosensory organs responsible for responding to changes in the chemical composition of the environment. Decreases in O₂ (hypoxia) as well as elevated CO₂ (hypercapnia) and acidosis in particular are detected by CB ‘glomus’ or ‘type I’ cells, which depolarise and release a host of neurotransmitters to modulate carotid sinus nerve (CSN) transmission and trigger rapid adaptive cardiorespiratory reflexes, including sympatho-excitation (Paton et al., 2013a), hyperventilation and increased mean arterial blood pressure (MABP). Several chronic diseases underpinned by sympathetic overactivity including hypertension (Abdala et al., 2012; McBryde et al., 2013), heart failure (Schultz et al., 2013), obstructive sleep apnoea (Del Rio et al., 2016), and metabolic disorders linked to insulin resistance (Conde et al., 2014; Conde et al., 2017) are thought to be at least partly caused by maladaptive alterations in chemoreflex sensitivity (Koeners et al., 2016). As a proof of concept, surgical techniques such as resection or denervation of the CB have had some success in attenuating the severity or the progression of these sympatho-excitatory diseases (McBryde et al., 2013; Pijacka et al., 2016a; da Silva et al., 2018; Niewinski et al., 2016; Del Rio et al., 2013; Ribeiro et al., 2013) highlighting the relevance of the CB as a therapeutic target. Yet these techniques are not without risk, and surgical intervention seems a somewhat blunt tool. We believe that a more detailed and integrated understanding of the cellular, molecular and genetic factors that guide and orchestrate these physiological changes in function such as hypersensitivity and tonicity could enable a subtler approach to tackling these disorders. Progressive and exciting new insights have recently highlighted a critical role for altered purinergic signalling within the CB-petrosal neuron interface in hypertension, where pharmacological and genetic inhibitors of purinergic signalling have been shown to successfully normalise the chemoreflex overactivity associated with hypertension in rat (Pijacka et al., 2016b) and canine models (Xue et al., 2020). Clinical development and human trials are now underway (Cully, 2016). It is now clear that the increase in CB signal transduction seen in cardiovascular diseases is underpinned by an overexpression of petrosal-localised purinergic P2X3 receptors (Pijacka et al., 2016b). We hypothesise that elevations in extracellular adenosine 5′-triphosphate (eATP) may also contribute to CB overactivity providing an intriguing new avenue for investigation.