Pharmacology of P2X receptors

Abstract

P2X receptors are ligand-gated cation channels that mediate many of the extracellular actions of adenosine 5 -triphosphate (ATP). The genes encoding seven different P2X subunits, P2X1-7, have been cloned and when expressed alone all P2X subunits form functional receptors, except P2X6, which usually only assembles in a heteromeric form. Subunits can also interact with each other and to date seven functional heteromultimers with pharmacological and/or biophysical properties that differ from the individual homomultimers have been identified: P2X2/3, P2X4/6, P2X1/5, P2X2/6, P2X1/4, P2X1/2, and possibly P2X4/7. These are distributed widely throughout the body and are involved in many physiological and pathophysiological processes. ATP is an agonist at all subtypes and few selective agonists and no useful antagonists were available when P2X receptors were first defined. Subsequently, nonselective antagonists, such as suramin and PPADS, were discovered and since then, and particularly in the past decade, numerous potent and subtype-selective antagonists have been developed. These include NF449 and RO-1 at P2X1 receptors; PSB-1011 at P2X2 receptors; A317491, compound A, RO-3, and AF-353 at P2X3 and P2X2/3 receptors; 5-BDBD at P2X4 receptors; and A740003, A438079, A804598, GSK314181A, AZ10606120, AZ11645373, AZD-9056, CE-224535, and EVT-401 at P2X7 receptors. The therapeutic usefulness of these compounds is currently being investigated in a variety of disorders, including thrombosis (P2X1), chronic neuropathic and inflammatory pain (P2X3, P2X2/3, P2X4, P2X7), dysfunctional urinary bladder (P2X1, P2X3, P2X2/3), rheumatoid arthritis and osteoarthritis (P2X7), and depression (P2X7). 

Identification of Contractile P2Y1, P2Y6, and P2Y12Receptors in Rat Intrapulmonary Artery Using Selective Ligands

“…In contrast, a maximally effective concentration of AR-C69931MX (1 M) had no significant effect on contractions elicited by KCl (40 mM) (94.5 Ϯ 3.7% of control; n ϭ 6) or UDP (300 M) (95.7 Ϯ 1.5% of control; n ϭ 3). Our previous data indicated that P2X1 receptors mediate more than half of the response to ATP (Chootip et al, 2002(Chootip et al, , 2005, and, consistent with this, the contractions elicited by ATP (300 M) were virtually abolished by the combined blockade of P2X1 and P2Y 12 receptors with the P2X1 antagonist NF449 (30 M) (Syed et al, 2010;Syed and Kennedy, 2012) and AR-C69931MX (1 M) (Fig. 2, c and d).…”

Purinergic signalling in the urinary tract in health and disease

“…For example, 3′-benzylamino-3′-deoxy-ATP was found to be very potent in the guinea-pig bladder, but was inactive at P2Y receptors. There are reviews that discuss the developments of P2X receptor antagonists [240,260,651].…”

Size matters in activation/inhibition of ligand-gated ion channels

“…Many P2XR antagonists have been identified [53–55], including a subtype non-selective, competitive antagonist called suramin. A mutational study [56] identified K138 in the human P2X1 receptor (corresponding to D141 in zP2X4R) as a possible suramin-interacting residue.…”

“…This lends support to the suggestion that competitive antagonists may occupy the wider inter-protomer ridge above the FCC (similar to ATP in the distal orientation), thereby maintaining the closure of the pre-M2 loop. Many other P2XR antagonists are described as noncompetitive, and their binding sites remain unknown [53–55]. …”