As just noted, myocyte excitability is regulated in part by changes in the electrochemical potential gradient across the plasma membrane. Before labor, myocytes maintain a relatively high interior electronegativity. Maintenance of a hyperpolarized membrane potential attenuates smooth muscle cell excitation and is regulated by ion channels.
Consistent with the importance of myometrial quiescence, numerous potassium channels control membrane potential. One key regulator is the large-conductance voltage-and Ca2+activated K channel (BKeJ (Perez, 1993). In normal physiology, the myometrial BKca channel plays dual and opposing
CRH, �2-sympathomimetics, 8 Oxytocin, thrombin,
Physiology of Labor 405
FIGURE 21 -6 Uterine myocyte relaxation and contraction. A. Uterine relaxation is maintained by factors that increase myocyte cyclic adenosine monophosphate (cAMP) levels. This activates protein kinase A (PKA) to promote phosphodiesterase activity with dephosphorylation of myosin light-chain kinase (MLCK). Other processes serve to maintain actin in a globular form and thus to prevent the fibril formation necessary for contractions. B. Uterine contractions result from reversal of these sequences. Actin now assumes a fibrillar form, and calcium enters the cell to combine with calmodulin to form complexes. These complexes activate MLCK to bring about phosphorylation of the myosin light chains. This generates ATPase activityto cause sliding of myosin over the actin fibrils, which is a uterine contraction. AC = + calcium; DAG = diacylglycerol; Gs and GQ = G-receptor proteins; IP3 = inositol triphosphate; LC20 = light chain 20; PIP3 = phosphatidylinositol 3,4,5-triphosphate;PLC = phospholipase C; R-PKA inactive protein kinase. (Redrawn from Smith R: Parturition. N Engl J Med. 2007 Jan 18;356(3):271-283.) roles to maintain a balance between uterine quiescence and contractility. The Bca channel is abundantly expressed in the myometrium. For most of pregnancy, opening the BKca channel allows potassium to leave the cell to maintain interior electronegativity, thus preventing voltage-gated Ca2+ inlux and contraction. Enhancing Bca channel opening results in myometrial relaxation, whereas inhibition ofthe Bca channel augments myometrial contractility. he ability of Bca channel to regulate calcium dynamics and ultimately uterine contractility from early to late gestation may result from temporal changes in expression ofthe Bca channel and/or Bca interacting partners (Wakle-Prabagaran, 2016).
Cellular signals that control myometrial contraction and relaxation can be efectively transferred between cells through intercellular junctional channels. Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling. The transmembrane channels that make up the gap junctions consist of two protein "hemi-channels" (Saez, 2005). These connexons are each composed of six connexin subunit proteins (Fig. 21-7). Of these, connexin-43 is expressed in myometrium, and concentrations rise near labor onset. Pairs of connexons establish a conduit between coupled cells for the exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions. Optimal numbers and types ofgap junctions are believed to be important for electrical myometrial synchrony.