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P2X receptor

P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.

Basic Structure and Nomenclature

Each functional P2X receptor is a trimer, with the three protein subunits arranged around an ion-permeable channel pore. To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X₁ through P2X₇.

receptor subtype	HUGO gene name	chromosomal location
P2X₁	P2RX1	17p13.3
P2X₂	P2RX2	12q24.33
P2X₃	P2RX3	11q12
P2X₄	P2RX4	12q24.32
P2X₅	P2RX5	17p13.3
P2X₆	P2RX6	22p11.21
P2X₇	P2RX7	12q24

The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X₆, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X₁ subunits is termed a P2X₁ receptor. The general consensus is that P2X₆ cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X₂ and P2X₃ subunits is known as a P2X_2/3 receptor.

The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.

Pharmacology

The pharmacology of a given P2X receptor is largely determined by its subunit makeup. Different subunits exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin. Of continuing interest is the fact that some P2X receptors (P2X₂, P2X₄, human P2X₅, and P2X₇) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG⁺) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation.

Tissue Distribution

P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission. Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X₁ receptors being particularly prominent in smooth muscle cells, and P2X₂ being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X₂ and P2X₃ subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X_2/3 receptors.

Physiological Roles

In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of physiological processes, including:

Modulation of cardiac rhythm and contractility
Modulation of vascular tone
Mediation of nociception - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X₄ in the spinal cord
Contraction of the vas deferens during ejaculation

Activation and Channel Opening

ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na⁺ and Ca²⁺ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca²⁺-sensitive intracellular processes. The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X₁ and P2X₃ receptors desensitize rapidly (a few hundred milliseconds) in the continued presence of ATP, whereas the P2X₂ receptor channel remains open for as long as ATP is bound to it. Three ATP molecules are thought to be required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore, though recent evidence suggests that ATP binds at the three subunit interfaces. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.

Allosteric Modulation

The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X₁, P2X₃ and P2X₄ receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X₂ is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X₂, P2X₃ and P2X₄, and inhibits currents through P2X₁. The allosteric modulation of P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain. In contrast to the other members of the P2X receptor family, P2X₄ receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin. Ivermectin potentiates ATP-gated currents through P2X₄ receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer.