Purinergic Signaling in Oral Tissues

Abstract

The role of the purinergic signal has been extensively investigated in many tissues and related organs, including the central and peripheral nervous systems as well as the gastrointestinal, cardiovascular, respiratory, renal, and immune systems. Less attention has been paid to the influence of purines in the oral cavity, which is the first part of the digestive apparatus and also acts as the body's first antimicrobial barrier. In this review, evidence is provided of the presence and possible physiological role of the purinergic system in the different structures forming the oral cavity including teeth, tongue, hard palate, and soft palate with their annexes such as taste buds, salivary glands, and nervous fibers innervating the oral structures. We also report findings on the involvement of the purinergic signal in pathological conditions affecting the oral apparatus such as Sjögren's syndrome or following irradiation for the treatment of head and neck cancer, and the use of experimental drugs interfering with the purine system to improve bone healing after damage. Further investigations are required to translate the results obtained so far into the clinical setting in order to pave the way for a wider application of purine-based treatments in oral diseases.

Keywords: dental structures; purine enzymes; purine receptors; purines; salivary glands; taste buds.

Figure 1

Mechanisms of purine release. ATP is released from cells in physiological conditions through multiple ways including vesicular exocytosis, connexin/pannexin (Cx/Panx) hemichannels, facilitated diffusion by nucleotide-specific ATP-binding cassette (ABC) transporters, and multiple organic anion transporters. In contrast, while most of the adenosine is formed from the nucleotide metabolism at extracellular level, the principal mechanism of adenosine efflux from cells is assured, under cell stress conditions, by carriers identified as equilibrative (ENT) and concentrative (CNT) nucleoside transporters. The former are bidirectional carriers, the direction of transport depending on the nucleoside concentration gradient across the plasma membrane, while the latter are Na⁺-dependent, being the nucleoside transport coupled to that of the sodium ion and independent of the nucleoside concentration gradient [27]. Additional transporters such as organic anion and cation transporters and ABC transporter proteins, have been implicated only as carriers of nucleoside-derived drugs, particularly those used as antiviral drugs [28].

Figure 2

Purinergic receptors. They are divided in two principal families named P1 and P2. The P1 receptor (P1R) family includes four subtypes (A₁R, A_2AR, A_2BR and A₃R), which are all metabotropic G proteins-coupled receptors [34]. The P2 receptor (P2R) family is subdivided into seven ionotropic P2X (P2XR), which are activated by ATP, and eight metabotropic P2Y receptors (P2YR), of which P2Y₁R respond to ATP and ADP, P2Y_2,4,6R are mainly activated by uridine-based nucleotides, P2Y_12,13R respond to ADP, and P2Y₁₄R to UDP-glucose (as recently reviewed by [35,36]). Ionotropic P2XR, when stimulated, allow the entry of cations such as Na⁺ and or Ca²⁺ into cells while metabotropic receptors belonging to the P1R family or to the P2YR subtypes are coupled to different G proteins and downstream molecular pathways indicated above. For major details see [37]. Abbreviations: AC, adenylate cyclase; cAMP, cyclic AMP, PLC/IP3-DAG, phospholipase C/inositol triphosphate-diacylglycerol.

Figure 3

Tooth anatomy. The tooth consists of three parts: crown, the visible part of the tooth; neck or collar, the part surrounded by the gingiva or gum, and root located inside the alveolar bone to which is linked by the periodontal ligament. The outer part of the crown is covered with a layer of dental enamel, the hardest element in the human body; below the enamel is dentin, the substance that gives the teeth their color and composed of about 70% of inorganic material, the remaining 30% of organic material and water. Dentin is generated by odontoblasts, cells contained in the pulp, which is inside the dentin and includes also the nerve and blood vessels. The periodontium is a set of structures that are located around the tooth and which have a dual function: to keep the tooth firmly in the alveolar bone and to preserve the integrity of the mucous membrane of the oral cavity. It is made up of four tissues: the gum, the periodontal ligament, the root cement and the alveolar bone itself, that is, that bone, also called the hard lamina, which delimits the dental alveolus.