Investigating the role of P2 receptors in uterine smooth muscle contraction has the potential to prove very useful in modern medicine. Knowing the involvement of these receptors in the control of up- and down- regulation of contractions and how they interact with agonists and antagonists will provide valuable information for dealing with the problems some women experience during and at the end of pregnancy. Hopefully with further study, adequate agonists and antagonists will be found that are suitable uterotonic drugs which could be used to either cease or induce uterine contractions, when necessary, in the safest possible way for both mother and child.
Smooth muscle is a specialized, non-striated tissue composed of contractile cells found in many vital organs throughout the body. It lines most of the hollow internal organs and is generally the supporting tissue found in arteries, veins, bladder, male and female reproductive organs, uterus, respiratory tract and the gastrointestinal tract .
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This type of muscle performs many diverse tasks throughout the different parts of the body. In blood vessels, smooth muscle helps regulate the blood flow around the body; it helps to regulate the movement of materials along internal passageways in the urinary and digestive tracts . As it contracts and relaxes in the respiratory passageways, the diameter is altered thus changing the resistance to airflow. Layers of smooth muscle can also help to move oocytes and possibly sperm along the reproductive tracts. The muscle in the walls of the uterus contracts and relaxes powerfully and rapidly during birth, expelling the foetus.
1.3 Mechanism of Contraction
The contraction of smooth muscle is involuntary. A Contraction can occur spontaneously and can be initiated by mechanical, electrical, and chemical stimuli. Contractions can either be described as phasic (rapid contraction and relaxation) or tonic (slow and sustained contraction).
Single-unit smooth muscle makes up the bulk of the muscle in most visceral organs. A high degree of electrical coupling between cells allows large regions of the tissue react as if they were a single cell. Gap junctions are the most effective structure in this type of coupling. In the uterus muscle, gap junctions are rare during pregnancy, the weak contractions seen during this period lack coordination, however there is a dramatic increase in both the number and size of gap junctions just prior to the onset of labour, and contractions appear stronger and more coordinated.
1.4 Uterine Smooth Muscle
Uterine contractility is generated by contractions of myometrial smooth muscle cells (SMCs) that compose most of the myometrial layer of the uterine wall . In the myometrium, as in other smooth muscle, contractile activity is initiated by a Ca2+ - calmodulin interaction which stimulates phosphorylation of the myosin light chain. RhoA/Rho kinase pathway signals a Ca2+ sensitization of the contractile proteins to inhibit the dephosporylation of the light chain by myosin phosphatase, thus maintaining the generation of force. Stimulation of myosin phosphatase and Removal of Ca2+ from the cytosol, initiate the process of smooth muscle relaxation.
Studies have shown, when investigating the role of Calcium store in uterine contractility, the smooth muscle cells have an internal Calcium store i.e. the sarcoplasmic reticulum (SR). The SR has a Ca-ATPase, called SERCA, which allows it to take up Ca ions from the cytoplasm into the lumen of the SR at the expense of ATP. There are two known types of release channels in the SR membrane; IP3-gated and Ca-gated (ryanodine) receptors. Both receptors have been noted in the uterus smooth muscle, but the IP3 receptors are seen to be more important in its contractile function .
It is also known, that in uterine smooth muscle, many pathways control the intracellular calcium concentrations and the contractile apparatus. One major pathway targets PLC activation, the release of intracellular calcium and stimulation of calcium entry. The production of diacylglycerol and inositol 1,4,5-trisphosphate (IP3) from phosphatidylinositide 4,5-bisphosphate (PIP2) is catalyzed by PLC enzymes. Calcium is released from intracellular stores when IP3 interacts with receptors on the endoplasmic reticulum. The release of calcium from these intracellular stores is hugely important for sustained contractile activity and is also an important component of the action of uterine contractions .
.5 Adenosine 5'-triphosphate
Figure 1.1 The chemical structure for Adenosine 5'-tri-phosphate, P2 receptor agonist 
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As we know, the contraction of smooth muscle is caused by the sliding action of actin and myosin filaments over each other. Hydrolysis of ATP provides the energy the cells need for this mechanism to occur. ATP is widely accepted as a signalling molecule in the body, and is recognised by purinoreceptors [7-10]. Extracellular ATP can stimulate contractile responses in visceral smooth muscle derived from organ types such as vas deferens, urinary bladder and myometrium. There is evidence that in the female reproductive tract, ATP, acting through P2 receptors, acts as a major non-adrenergic, non-cholinergic co-transmitter in mediating sympathetic regulation of contractile responses in smooth muscle .
Patch-clamp electrophysiological studies have verified that ATP can activate receptors that act as ligand-gated ion channels in smooth muscle cells that have been isolated from tissues such as pregnant rat myometrium .
The contractile activity of ATP in the uterus was highlighted in a study undertaken by Michelle Bardini in 2000. Using immunohistochemistry techniques, it was discovered that there was an abundance of P2Xâ‚‚ receptors present in the smooth muscle of the ovary and uterus as well as in blood vessels . ATP is a potent agonist of the P2X receptor family  .
Receptors for ATP and adenosine are widely distributed throughout the body in many different organs and tissues including the uterine smooth muscle. These surface receptors for extracellular nucleotides are known as purinoceptors . Two types of purinoceptors, P1 and P2 (for adenosine and ATP/ADP, respectively) were distinguished in 1978 ; two years after Purinergic receptors were first defined .
The P1/adenosine receptor family is subdivided, according to much biochemical and pharmacological evidence into the four subtypes; Aâ‚, A2A, A2B, and Aâ‚ƒ, all of which couple to G proteins [7, 16].
P2 receptors have been found on the cell membranes of numerous cell types, and there activation is the cause of many different types of physiological response. Abbracchio and Burnstock divided these P2 receptors into two main classes, the P2X and P2Y families. This was based on whether they are ligand-gated ion channels (P2X) or are G protein-coupled receptors (P2Y) . There are currently seven P2X receptor subtypes and eight P2Y receptor subtypes.
1.6.1 P2X Receptors
The P2X family ranges from P2Xâ‚ - P2Xâ‚‡, the subunit topology consists of intracellular N- and C- termini with binding motifs for protein kinases; two transmembrane spanning regions involved in channel gating and lining the ion pore; a large extracellular loop with cysteine residues forming a series of disulphide bridges; a hydrophobic H5 region for possible receptor/channel modulation by cations; and an ATP-binding site. It has been thought that the disulphide bridges may form the structural constraints needed to couple the ATP-binding site to the ion pore . P2X receptors create ion-selective channels to extracellular fluid thus increasing [CaÂ²âº]áµ¢ levels . In 2002 Ziganshin hypothesised that the P2 receptors in pregnant human uterus are members of the P2X family .
1.6.2 P2Y Receptors
The P2Y receptor topology differs somewhat to that of the P2X receptors. They are characterised by an extracellular N-terminus and intracellular C-terminus which holds binding motifs for protein kinases; seven transmembrane spanning regions which aid in the formation of a ligand docking pocket. The P2Y receptors are bound to single heterotrimeric G proteins . The receptors in the P2Y family are P2Yâ‚, P2Yâ‚‚, P2Yâ‚„, P2Yâ‚† and P2Yâ‚â‚ . The P2Y receptors increase [CaÂ²âº]áµ¢ levels by causing the release of CaÂ²âº from the SR .
1.7 Role of P2 Receptors in Smooth Muscle contraction
Continual study is being carried out to completely understand the role of P2 receptor activity in smooth muscle cells (SMCs), along with the effects their agonists and antagonists have on muscle contraction. The diversity of the results discovered in some studies, enlighten us with some knowledge on the characteristics of P2 receptor, and how their interactions with different agonists and antagonists can greatly affect the contraction of various tissues in the body. The P2 receptors function to increase calcium concentration in the cytoplasm and are activated by binding of the receptor to ATP or to other receptor agonists.
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Airat U. Ziganshin investigated P2 receptor characteristics in the human uterus in 2002 . It was found that ATP produced dose-dependent contractions of pregnant myometrium but no such result was seen in non-pregnant tissue. His study also showed that the amplitude of contractions produced by agonists was severely decreased when treated with a known P2 receptor antagonist. In 2007 the same group studied the 'contrasting effects of P2 receptor agonists on spontaneous contractility of human fallopian tubes with and without acute inflammation'. From this study it was seen that P2 receptor agonists like ATP can have an effect on the spontaneous activity of isolated human uterine tubes. Most of the tested agonists of P2 receptors, to a greater or lesser extent, increased the contractile activity.
It is clear from previous studies like these that P2 receptor agonists can adjust contractile force through activation of P2 receptors . Another study that further examined this process was undertaken by Miyuki Nagaoka in 2009. It investigated the effect of P2 receptors in the smooth muscle contraction of tracheal tissue. The effects of extracellular ATP on single airway caused a sustained inward current after stimulation of P2Xâ‚„ receptors. It was seen that the receptors and their agonists work in a similar way to the mechanism of contraction regulation in uterine smooth muscle. It was found in this study that direct CaÂ²âº entry through P2Xâ‚„ receptors caused the contractile response .
1.8 PPADS & MRS2159: P2 Receptor Antagonists
There is a wide range of P2 receptor agonists and antagonists that are very well established today. As I have already outlined, ATP is a potent agonist of the P2X receptor family. The lesser known pyridoxal-5'-phosphate 6-azophenyl 2', 4'-disulfonate (PPADS) is an effective and selective antagonist to this same group. Another antagonist is MRS2159 which is a potent and selective blocker of P2Xâ‚ receptors.
Figure 1.2 The chemical structure for PPADS, P2 receptor antagonist 
PPADS in a known non-selective P2 receptor antagonist , like any receptor antagonist it doesn't show any biological response itself in the tissue but dampens or even blocks the agonist-mediated responses on contraction. This is supported by studies done such as that of Airat U. Ziganshin in 2003, where it was found that PPADS significantly reduced the contractile responses evoked by P2 receptor agonists .
MRS2159 is noted to be a more potent derivative of PPADS where its antagonist effects are seen to be increased in P2xâ‚ receptors (7-fold) and P2xâ‚ƒ receptors (2-fold) .
The role played by P2 receptors in uterine smooth muscle contraction is obvious, and it is also clear there are numerous agonists and antagonists that can interact with these receptors to alter the regulation of the muscle contraction.
Uterotonic drugs stimulate uterine contractions. It is known that drugs such as oxytocin and ergometrine have strong uterotonic properties and are regularly used to prevent or treat uterine atony and reduce the quantity of blood lost during and after childbirth. These drugs have also been widely used for the induction of labour and in the prevention of postpartum haemorrhage. With the growing knowledge of P2 receptor properties in uterine smooth muscle contraction, the introduction of agonists and antagonists such as ATP, PPADS and MRS2159 as a suitable uterotonic drugs would be highly valuable to modern medicine, as some risks are associated with the administration of drugs such as oxytocin to induce labour. Severe labour contractions can occur, which if too strong can deprive the baby of oxygen thus causing foetal distress.
Hopefully with further research, suitable uses for agonists and antagonists of P2 receptors will be discovered, which will develop into effective and reliable methods of inducing/ ceasing spontaneous myometrial contraction in modern medicine.