Intracellular Messengers Regulating Parathyroid Hormone Release

Regulation of hormone release involves translation of extracellular signals through interacting second messenger systems such as cytoplasmic Ca2+j, cAMP, and diacylglycerol production through phosphoinositol hydrolysis. It has been demonstrated that external calcium acts through all of these messenger systems of the parathyroid cell.31 Calcium interferes with parathyroid adenylate cyclase and cAMP-dependent protein kinases.32 This mode of action has been seen in many agents besides calcium and other cations that stimulate or inhibit PTH release.1 It is unlikely, however, that the regulation of parathyroid cell secretion by external calcium is controlled principally through cAMP-dependent mechanisms.

The same conclusion has been drawn for the pathologic parathyroid tissue of patients with HPT, despite its altered adenylate cyclase activity.2 It has also been demonstrated that cAMP appears to regulate the release of PTH that is less newly synthesized than that secreted under the influence of external calcium.33 Although guanidine nucleotide-binding (G) proteins regulate cAMP production, the role of G proteins in regulating parathyroid Ca2+j and PTH release is unclear.34

A rise in extracellular calcium momentarily elevates Ca2+j to an unusually high level in normal human parathyroid cells.4'35 As with calcium-regulated PTH secretion, there is a sigmoidal but positive dose-response relationship between Ca2* and external calcium (see Fig. 39-1B). The midpoints of these dose-response curves for calcium-regulated secretion and Ca2+, are correlated. Half-maximal inhibition of PTH release is attained at lower external calcium concentrations than the corresponding elevation of Ca2+j. Moreover, the secretion is inversely and linearly related to Ca2+i within essentially physiologic and supraphysiologic concentrations of calcium.36 In the very low concentration range of external calcium, however, both Ca2* and PTH release are stimulated by a rise in external calcium. A stepwise increase in external calcium elicits a biphasic Ca2+j response in normal parathyroid cells (Fig. 39-4A). This response consists of a rapid Ca2+j transient peak followed by a slower steady-state elevation, which seems to persist for as long as the external stimulus is maintained. The rapid Ca2* peak may also be induced in the absence of external calcium by inositol 1,4, 5-triphosphate-mediated release of intracellular calcium from

1000

1000

Time (sec)

Time (sec)

30 60

Time (sec)

tu O

30 60

Time (sec)

FIGURE 39-4. Effects of stepwise increases in extracellular calcium from 0.5 to 3.0 mmol/L on cytoplasmic calcium (A) and parathyroid hormone (PTH) release (B) of normal bovine parathyroid cells loaded with intracellular concentrations of fura-2 of about 0.1 (O) and 0.5 (•) mmol/L. PTH and extracellular calcium concentrations in the perfusate were measured in 5-second samples. PTH release is expressed in percentages of the initial secretion at 0.5 mmol/L extracellular calcium. Values represent mean ± standard deviation. (From Wallfelt C, Lindh E, Larsson R, et al. Kinetic evidence for cytoplasmic calcium as an inhibitory messenger in parathyroid hormone release. Biochim Biophys Acta 1988;969:257. Reprinted with permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, The Netherlands.)

the endoplasmic reticulum.37 38 In contrast, the steady-state Ca2+j elevation depends on calcium influx through the plasma membrane.439 This permeability change may be caused by a calcium-mediated increase in inositol tetra-kisphosphate. Improvements in the technical handling of parathyroid cells have confirmed that the steady-state Ca2+j elevation actually consists of rather impressive oscillations in the calcium concentration (unpublished data). The frequency, but not amplitude, of these oscillations is regulated by external calcium, and the oscillations are sensitive to calcium channel blockers (Fig. 39-5). Such oscillations are expected to enhance the sensitivity of calcium-regulated Ca2+j and PTH release and to reduce intracellular exposure to potentially damaging steady-state elevations in Ca2+r Moreover, a direct relationship between synchronized Ca2+, oscillations and pulsatile hormone release has been established in other cell systems.40

A strong argument for Ca2+, as the principal regulator of PTH release has been built by studies of the kinetics of PTH regulation by calcium.4 Parathyroid cells equipped experimentally with low calcium-buffering capacity demonstrated a momentary rise in Ca2+P which rapidly reached a steady-state level upon a stepwise increase in external calcium (see Fig. 39-4). Cells provided with higher buffering capacity, however, displayed slower calcium-induced rises in Ca2+j and sluggish alterations in PTH release. High extracellular calcium also increases hydrolysis of the phosphoinositides into not only inositol trisphosphates but also diacylglycerol, whereby activation of classic protein kinase C is expected to occur. Protein kinase C activation at low extracellular calcium concentrations inhibits PTH release but stimulates PTH secretion at high external calcium levels.41 The role of protein kinase C in PTH secretion remains to be elucidated because there is discordant activation of protein kinase C at low and inositol trisphosphate at high external calcium levels.42,43

Electrophysiologic analyses have demonstrated that inhibition of PTH release by high external calcium levels is associated with depolarization of the parathyroid cell.44 Studies of transmembrane calcium fluxes, however, revealed that calcium influx occurs through a calcium-activated and voltage-independent permeability and that calcium influx current

FIGURE 39-5. Microfluorometric measurement of the cytoplasmic calcium concentration in a normal human parathyroid cell exposed to stepwise increases in the extracellular calcium concentration from 0.5 to 2.5 mmol/L (upper scale). Frequency of the rhythmic Ca2+j oscillations depends on the external calcium concentration, and they are abolished by presence of the inorganic calcium channel blocker cerium (200 pmol/L).

FIGURE 39-5. Microfluorometric measurement of the cytoplasmic calcium concentration in a normal human parathyroid cell exposed to stepwise increases in the extracellular calcium concentration from 0.5 to 2.5 mmol/L (upper scale). Frequency of the rhythmic Ca2+j oscillations depends on the external calcium concentration, and they are abolished by presence of the inorganic calcium channel blocker cerium (200 pmol/L).

causes the depolarization.39 A calcium receptor on the parathyroid cell surface was postulated. This receptor was unusual in that a verapamil analog, which blocks voltage-sensitive calcium channels, would stimulate calcium influx and raise the Ca2+j of the parathyroid cells.45 Several other divalent cations (e.g., magnesium) can cause transient rises in Ca2+i by intracellular mobilization. Even the trivalent cation lanthanum, which is restricted to the cell exterior, may raise parathyroid Ca2* and inhibit hormone release.46 These findings provide additional arguments for the presence of a surface cation sensor on the parathyroid cell. Activation of this sensor seems to regulate phosphoinositol metabolism and protein kinase C activity, whereas G protein involvement in the messenger cascade is questionable. Moreover, Ga3+ inhibits PTH release by an apparently different mechanism from the sensor coupled to Ca2+r47 Consequently, there may be several cation-sensitive mechanisms involved in the regulation of PTH secretion. Indeed, it has been postulated that proteins with calcium receptor function are expressed not only on parathyroid cells but also on proximal kidney tubule cells, placental cytotrophoblasts, surfactant-producing alveolar pneumocytes, and thyroid C cells.31'48 Such sensors may thus be widely distributed and function at several sites in systemic and cellular calcium homeostasis.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment