Ca2+ Transport Across Plasma and Intracellular Membranes Is an Important Second Messenger
The transport of Ca2' ions through gated channels across the plasma membrane and across intracellular membranes (e.g., endoplasmic reticulum) is a major second messenger system for physiological information transfer.
Fhe available evidence suggests that the major role of Ca2* within cells is as a physiological signal. In the extracellular compartment, the major physiological function of Ca is as the principal mineral of bone. Ca^+ is an excellent ion for use as a second messenger because the cytoplasmic concentration of Ca~i is extremely low, about 10' mol/L in a resting cell. Increases in intracellular Ca2' concentration can be (1) detected easily because the background noise is so low and (2) achieved easily because the Ca2+ concentration [Ca2* ] in the ECF and in some cellular compartments, such as the endoplasmic reticulum and mitochondria, is IO4 higher than in the cytoplasm (see Table 1-1). Thus, there is an enormous driving force for Ca2+ diffusion into the cytoplasm under most conditions.Although many GPCRs use Ca2* as one part of their intracellular pathway, the interaction is more complex than usual, as discussed shortly. Thus, we focus here on a simpler and very important example of Ca2t as a second messenger that has already been discussed: the role of Ca2, in regulating the actomyosin Al Pase of muscle.
Increased [Ca2*] in the cytoplasm alters cellular function by binding to any of several Ca2+-Iiinding proteins that serve as control proteins. Troponin is one Ca2,-binding protein already mentioned. Reviewing the example of striated muscle contraction from the Ca2* point of view, Ca2* (second messenger) diffuses through gated channels in the endoplasmic- reticulum (sarcoplasmic reticulum) of muscle in response to electrical events (first message) on the plasma membrane of the muscle cell.
The diffusion of Ca2* from the concentrated storehouse of the sarcoplasmic reticulum increases [Ca2*] in the cytoplasm of the muscle cell, where it binds to troponin. On binding Ca2+, troponin changes its interaction with tropomyosin, which now moves to allow myosin heads access to the actin of the thin filament. The actomyosin Al Pase is activated, and muscle contraction ensues.Cabnoduliii is a Ca2+-binding protein that plays an important control function in almost all animal cells. As with troponin, calmodulin binds Ca2i when the cytoplasmic [Ca2* ∣ increases. The Ca-tZcaImoduIin complex activates a large number of different cellular processes. In most such cases, but not all, the Ca24Zcalmodulin complex binds to and activates an enzyme. One such enzyme, a protein kinase, is involved in the excitation-contraction coupling in smooth muscle (Figure 1-17), not discussed earlier with the striated muscle types. Protein kinases in general catalyze the hydrolysis of ATP and couple it to the simultaneous phosphorylation of other proteins, as follows:
Ca24ZcaImoduIin activated
ATP + Protein → Protein phosphate + ADP Protein kinase
In the case of smooth muscle, the particular protein kinase is myosin kiιτase, which, as its name implies, specifically phosphorylates myosin. Ihis phosphorylation increases the affinity of the myosin heads for actin filaments; thus allowing cross-bridging to actin. On formation of the cross-bridge, myosin strokes past the thin filament, producing filament sliding, contraction, and force production by smooth muscle. Cessation of contraction is achieved by cleavage of the phosphate from the myosin by another enzyme, myosin phosphatase.
Thus, initiating smooth muscle contraction involves a Rube Goldberg sequence in which environmental stimulation of a smooth muscle cell causes an increase in the intracellular [Ca2+1, the second messenger. This in turn leads to a cascade of cause and effect. Increased intracellular [Ca2f] causes calmodulin to bind Ca2*. The Ca2VcalmoduIin complex activates the myosin kinase. This enzyme phosphorylates the myosin head, allowing it to cross-bridge to actin. Cross-bridging leads to actomyosin activation, causing filament sliding that is observed as muscle contraction at the tissue level.
This discussion of Ca2* as a second messenger emphasizes one of its major physiological functions: as the second messenger responsible for mediating contraction for all types of muscle (skeletal, cardiac, and striated), although the details of each pathway differ.