The quiescence of phase 1 likely stems from: (1) actions of estrogen and progesterone via intracellular receptors, myometrial-cell plasma membrane receptor-mediated increases in cyclic adenosine monophosphate (cMIP), generation of cyclic guanosine monophosphate (cGMP), and (4) other systems, including modiication of myometrial-cell ion channels.
The balance between myometrial relaxation and contraction is controlled by steroid-and peptide-hormone transcriptional regulation of key genes and their protein products. Quiescence is achieved in part by: (1) diminished intracellular crosstalk and reduced intracellular Ca2+ ([Ca2+J levels; (2) ionchannel regulation of cell membrane • Myometrium is major site of action • Cervix is major site • Both are sites of action
Phase 1 Phase 2 Phase 3 Uterine stretch Gap junction receptors Fetal signals (SPA, PAF, CRH) Fetal membrane Prostaglandins Cortisol? Phase 4
FIGURE 21-5 The key factors thought to regulate the phases of human parturition. CRH = corticotropin-releasing hormone; hCG i.):D o:sD)
CRH?
potential; (3) activation of the uterine endoplasmic reticulum stress-unfolded protein response; and (4) uterotonin degradation. In contrast, contractility results from: (1) enhanced interactions between the actin and myosin proteins; (2) heightened excitability of individual myometrial cells; and (3) promotion of intracellular crosstalk that allows synchronous contractions to develop.
Actin and myosin proteins are essential to muscle contraction. For this, actin must be converted from a globular to a ilamentous form. Indeed, a potential mechanism for maintenance of relaxation is the promotion ofactin into a globular form rather than into ibrils, which are required for contraction (Fig. 21-6). Moreover, actin must be attached to the cytoskeleton at focal points in the cell membrane to allow tension to develop.
Actin must partner with myosin, which is composed of multiple light and heavy chains. The coupling of myosin and actin activates adenosine triphosphatase (ATPase), hydrolyzes adenosine triphosphate, and generates force. This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain of myosin (Stull, 1998). his is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium. Calcium binds to calmodulin, a calcium-binding regulatory protein, which in turn binds to and activates myosin lightchain kinase.
hus, logically, uterine relaxation ordinarily is promoted by conditions that lower concentrations of (Ca2+)i. In contrast, prostaglandin dehydrogenase; SPA surfactant protein A.
agents that prompt contraction act on myometrial cells to augment (Ca2+)i levels. Or, they allow an inlux of extracellular calcium through ligand-or voltage-regulated calcium channels (see Fig. 21-6). Voltage-gated ion channels open, additional calcium ions move into the cell, and cellular depolarization follows. For example, prostaglandin F2ex and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels. Activation of these receptors also releases calcium from the sarcoplasmic reticulum to lower electronegativity within the cell. Additionally, greater localization of nonselective cation channels on the cell membrane promotes Ca2+ entry (Ying, 2015). The rise in (Ca2+)i levels is often transient. But, contractions can be prolonged by inhibition of myosin phosphatase, an enzyme which dephosphorylates myosin (Woodcock, 2004).
Regulation of Membrane Potentials