This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

/pdf/physiology-and-pathophysiology-of-purinergic-1z94g2hz0f.pdf

Physiology and Pathophysiology of Purinergic Neurotransmission

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

/pdf/cellular-distribution-and-functions-of-p2-receptor-subtypes-32555c8g2p.pdf

Cellular distribution and functions of P2 receptor subtypes in different systems.

The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article.

Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

Using functional co-cultures of rat carotid body (CB) O2 chemoreceptors and ‘juxtaposed’ petrosal neurones (JPNs), we tested whether ATP and ACh acted as co-transmitters.


Perforated-patch recordings from JPNs often revealed spontaneous and hypoxia-evoked (PO2≈5 mmHg) excitatory postsynaptic responses. The P2X purinoceptor blocker, suramin (50 μM) or a nicotinic ACh receptor (nAChR) blocker (hexamethonium, 100 μM; mecamylamine, 1 μM) only partially inhibited these responses, but together, blocked almost all activity.


Under voltage clamp (-60 mV), fast perfusion of 100 μM ATP over hypoxia-responsive JPNs induced suramin-sensitive (IC50 = 73 μM), slowly-desensitizing, inward currents (IATP) with time constant of activation τon = 30.6 ± 4.8 ms (n = 7). IATP reversed at 0.33 ± 3.7 mV (n = 4), and the dose-response curve was fitted by the Hill equation (EC50 = 2.7 μM; Hill coefficient ≈0.9). These purinoceptors contained immunoreactive P2X2 subunits, but their activation by α,β-methylene ATP (α,β-meATP; EC50 = 2.1 μM) suggests they are P2X2/P2X3 heteromultimers.


Suramin and nAChR blockers inhibited the extracellular chemosensory discharge in the intact rat carotid body-sinus nerve preparation in vitro. Further, P2X2 immunoreactivity was widespread in rat petrosal ganglia in situ, and co-localized in neurones expressing the CB chemo-afferent marker, tyrosine hydroxylase (TH). P2X2 labelling in the CB co-localized with nerve-terminal markers, and was intimately associated with TH-positive type 1 cells.


Thus ATP and ACh are co-transmitters during chemotransduction in the rat carotid body.







In mammals, an early step in the initiation of compensatory reflex hyperventilation during blood hypoxaemia appears to involve neurotransmitter release from O2-sensitive chemoreceptor (type 1) cells in the carotid body onto apposed sensory nerve endings (reviewed by Gonzalez et al. 1994). Excitation of these endings by released transmitter(s) is proposed to result in the increased afferent spike discharge in the carotid sinus nerve, whose chemo-afferent cell bodies are located in the petrosal ganglion. A long-standing, unresolved issue is the identity of the neurotransmitter(s) initiating this reflex (Gonzalez et al. 1994; Fitzgerald et al. 1997). Whereas the best studied carotid body neurotransmitter dopamine has recently fallen into disfavour (e.g. Donnelly, 1996), there has been a rekindling of interest in ACh as a major carotid body neurotransmitter during chemo-excitation, even though it too has had a long and controversial history (Gonzalez et al. 1994; Fitzgerald et al. 1997; Nurse & Zhang, 1999).

In order to probe these transmitter mechanisms, we recently developed an attractive co-culture preparation consisting of dispersed rat type 1 cell clusters and dissociated petrosal neurones (Zhong et al. 1997; Nurse & Zhang, 1999). The main advantages are that: (i) functional connections develop de novo; (ii) subthreshold synaptic events can be conveniently studied by recording from petrosal somas, juxtaposed to type 1 cell clusters; and (iii) drugs have relatively unrestricted access to the synaptic sites under these monolayer conditions. Using this preparation we recently provided strong evidence for ACh as a co-released transmitter from type 1 cells during chemosensory signalling (Zhong et al. 1997; Nurse & Zhang, 1999). We further characterized the properties of the nicotinic ACh receptors (nAChR) expressed by petrosal neurones using pharmacological and electrophysiological techniques (Zhong & Nurse, 1997). However, it was evident that ACh alone could not account entirely for the hypoxia-induced ‘postsynaptic’ responses recorded in co-cultured neurones. We therefore considered the possibility that other co-released transmitters might be involved.

An attractive candidate for an excitatory, sensory co-transmitter in carotid body function is ATP. First, the excitatory effects of ATP on carotid body chemosensory fibres have been recognized for some time, based on sinus nerve recordings during intracarotid injections of ATP (Jarish et al. 1952; Spergel & Lahiri, 1993). Second, ATP is frequently co-released with ACh in several neuronal preparations (Schweitzer, 1987; Bean, 1992; Zimmerman, 1994; Silinsky & Redman, 1996), and purinoceptors are widely distributed on sensory neurones and their terminals (Khakh et al. 1995; Lewis et al. 1995; Vulchanova et al. 1996; Wildman et al. 1997). Third, cation-selective P2X purinoceptor channels were first described in the peripheral nervous system, where they appear to be important for mediating fast excitatory neurotransmission at a variety of synapses (Surprenant et al. 1995).

In the present study we identified an important role for ATP as a co-transmitter in carotid body function, based largely on the sensitivity of the afferent postsynaptic responses to the P2 purinoceptor blocker suramin. However, since suramin blocks both ligand-gated P2X and G-protein-coupled P2Y purinoceptors (Dunn & Blakely, 1988; Evans et al. 1992), we carried out a more detailed characterization of the P2 receptor subtype(s) expressed by chemosensory petrosal neurones using electrophysiological, pharmacological and immunofluorescence techniques. In addition, in order to validate the results obtained from co-cultures, we compared the effects of both nicotinic cholinergic and purinoceptor blockers on the afferent discharge recorded from the intact rat carotid body sinus nerve preparation in vitro (Pepper et al. 1995; Donnelly, 1996). These combined data led to the conclusion that co-release of ATP and ACh, acting at postsynaptic P2X2-containing and nicotinic-ACh receptors, respectively, plays a dominant role in rat carotid body PO2 chemotransmission.

Co‐release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1954.sp005143

Observations on the volume of blood flow and oxygen utilization of the carotid body in the cat.

Impulse Activity in the Carotid Sinus Nerve following Intra‐carotid Injection or Potassium chloride, Veratrine, Sodium citrate, Adenosine‐triphosphate and α‐Dinitrophenol

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Impulse Activity in the Carotid Sinus Nerve following Intra‐carotid Injection or Potassium chloride, Veratrine, Sodium citrate, Adenosine‐triphosphate and α‐Dinitrophenol