CHRONIC RENAL FAILURE—Its Effect on Calcium,Phosphorus and Osseous Metabolism; A Unified Approach

The renal osteodystrophies represent the metabolic consequences of (1) vitamin D resistance, (2) secondary hyperplasia of the parathyroids, and (3) the changes in serum PO₄= and Ca++ secondary to the renal insufficiency per se.The osseous lesion in any given patient with chronic renal failure may be osteitis fibrosa, rickets (osteomalacia), calcium deficiency osteoporosis or any combination of these. The concentration of Ca++ and PO₄= in the serum is determined by the degree of renal failure and the skeletal response to parathyroid hormone.     

Effects of divalent cations on dynein cross bridging and ciliary microtubule sliding

We recently demonstrated that addition of the divalent cation Mg++ to demembranated cilia causes the dynein arms to attach uniformly to the B subfibers. We have now studied the dose-dependent relationship between Mg++ or Ca++ and dynein bridging frequencies and microtubule sliding in cilia isolated from Tetrahymena. Both cations promote efficient dynein bridging. Mg++-induced bridges become saturated at 3 mM while Ca++-induced bridges become saturated at 2 mM. Double reciprocal plots of percent bridging vs. the cation concentration (0.05-10 mM) suggest that bridging occurs in simple equilibrium with the cation concentration. When microtubule sliding (spontaneous disintegration in 40 mM N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid (HEPES), 0.1 mM ATP at pH 7.4) is assayed (A350 nm) relative to the Mg++ or Ca++ concentration, important differential effects are observed. 100% Disintegration occurs in 0.5-2 mM Mg++ and the addition of 10 mM Mg++ does not inhibit the response. The addition of 0.05-10 mM Ca++ to cilia reactivated with 0.1 mM ATP causes a substantial reduction in disintegration at low Ca++ concentrations and complete inhibition at concentrations greater than 3 mM. When Ca++ is added to cilia reactivated with 2 mM Mg++ and 0.1 mM ATP, the percent disintegration decreases progressively with the increasing Ca++ concentration. The addition of variable concentrations of Co++ to Mg++-activated cilia causes a similar but more effective inhibition of the disintegration response. These observations, when coupled with the relatively high concentrations of Ca++ or Co++ needed to inhibit disintegration, suggest that inhibition results from simple competition for the relevant cation-binding sites and thus may not be physiologically significant. The data do not yet reveal an interpretable relationship between percent disintegration, percent dynein bridging, and percent ATPase activity of both isolated dynein and whole cilia. However, they do illustrate that considerable (sliding) disintegration (60%) can occur under conditions that reveal only 10-15% attached dynein cross bridges.     

Calcium-mediated decrease of a voltage-dependent potassium current.

Elevated intracellular Ca++ concentration reduces the amplitude of an early, voltage-dependent K+ current (IA) in the Type B photoreceptor of Hermissenda crassicornis. Internal Ca++ is increased by activating a voltage and light-dependent Ca++ current present in these cells or by direct iontophoresis of Ca++ ions. Substitution of Ba++ for Ca++ or elimination of Ca++ from the sea water bathing the cells abolishes the reduction in IA during paired light and depolarizing voltage steps. The delayed K+ current (IB) in these cells is also reduced during paired light and voltage steps, but this decrease of IB is not affected by removal of extracellular Ca++. IB (but not IA), apparently much less dependent on intracellular Ca++ levels, is reduced by light alone. Ca++ iontophoresis also abolishes the light-dependent Na+ current, which recovers with a time course of minutes.     

Ca^2＋与细胞凋亡

Ｃａ＾２＋在某些因素诱导的细胞凋亡中起着重要信使作用。细胞内Ｃａ＾２＋浓度上升可来源于胞外Ｃａ＾２＋内汉、内库钙动员或者二者兼之。     

"Calcium antagonists": a class of drugs with a bright future. Part I. Cellular calcium homeostasis and calcium as a coupling messenger

The aim of this series of minireviews is to present material from multidisciplinary sources to facilitate the understanding of the pharmacology and the ample clinical potential of a class of drugs that were originally designated as "calcium antagonists" and more recently have been referred to as "calcium entry blockers", "calcium slow channel blockers" or "calcium modulators". In this first report our attention will be focussed on the pivotal role of Ca++ as a messenger linking stimuli of extracellular origin to the intracellular environment. Eucaryotic cells have a number of powerful means to control their cytosolic Ca++ concentration. Firstly, in a cell at rest the cellular membrane is relatively impermeable to passive Ca++ movements. This property of the plasmalemma prevents the high free Ca++ concentration (approximately 1 mM) of the extracellular compartment from invading the cytosol (approximately 0.1 microM). However, extracellular Ca++ can reach the cytosol through the Na+/Ca++ exchange mechanism and the plasmalemma possesses special Ca++ channels the conductance of which is controlled by gates that are opened by critical changes in cellular polarization (voltage-operated channels: VOC) or by receptor activation (receptor-operated channel: ROC). The Ca++ entering via VOC or ROC can subsequently trigger the liberation of Ca++ from the sarcoplasmic reticulum or from calcium stores located in the inner side of the plasmalemma. The intracellular message generated by external stimuli is transferred to the response mechanism by several cytosolic proteins that require Ca++ as activator. Finally, the termination of the response is the result of a reduction in the cytosolic Ca++ concentration that is accomplished by the Na+/Ca++ exchange mechanism or by energy-dependent pumps which extrude Ca++ from the cell or store it in subcellular organelles. Therefore, any of the numerous steps of the excitation-response coupling which employ Ca++ as a messenger or as a protein activator can be the site of action of a pharmacological agent. In the follow-up minireview, some methods to determine the basic pharmacological profile of compounds interfering with cellular Ca++-dependent functions will be described.     

The blocking effect of magnesium on the secretion of adrenal catecholamines induced by the omission of sodium from the extracellular medium.

The blocking action of Mg++ on catecholamine release induced by the substitution of extracellular Na+ by an osmotic equivalent amount of sucrose was studied in isolated, perfused bovine adrenal glands. Perfusing glands with 10 mM Mg++ produced at 51.1% inhibition on catecholamine release evoked by Na+ omission. Increasing the concentration of Mg++ to 20 mM this inhibitory effect was enhanced to 90.3%. D-600 (0.3 mM) promoted a marked blockade of acetylcholine-induced release of catechol hormones that was partially and significantly reverted increasing the concentration of Ca++ in the perfusion medium. D-600 (0.3 mM) failed to inhibit the catecholamine-releasing effect of Na+ deprivation. In adrenal glands previously perfused with D-600 (0.3 mM) and then exposed to a Locke solution containing D-600 (0.3 mM) + Mg++ (10 or 20 mM) the inhibition of the secretory responses evoked by the omission of Na+ was of the same magnitude as that obtained when the glands were perfused with Mg++ (10 or 20 mM) in the absence of D-600. These results are compatible with the view that the blocking effect of Mg++ may involve an intracellular site of action and that the access of Mg++ into the chromaffin cell may not be mediated through the Ca++ channels.     

Divalent cations enhance ammonia excretion in Lahontan cutthroat trout in highly alkaline water

The Lahontan cutthroat trout lives under highly alkaline and saline conditions in Pyramid Lake, Nevada (pH 9.4; 0.2 mmol 1⁻¹ Ca⁺⁺; 7.3 mmol 1⁻¹ Mg⁺⁺). These experiments were conducted to study the possible roles of water Ca⁺⁺ and Mg⁺⁺ concentrations on ammonia excretion in the Lahontan cutthroat trout under highly alkaline conditions. The basic protocol of the experiments was to determine ammonia excretion rates during the following three exposure periods (each of 3-h duration) in sequence: (a) in normal lake water; (b) in soft lake water with the divalent cation concentrations reduced; and (c) in the soft lake water with either Ca⁺⁺ or Mg⁺⁺ (or no divalent cations added) added back at the appropriate lake water concentration. The soft-water exposure caused a significant reduction in ammonia excretion to about half of the control (original lake water) levels. When either Ca⁺⁺ or Mg⁺⁺ was added to the soft water in the third exposure period, the ammonia excretion rates were increased more than twofold back to lake water levels.     

Thrombin-induced calcium oscillation in human platelets and MEG-01, a megakaryoblastic leukemia cell line.

Digital imaging microscopy revealed that human platelets show periodic intracellular Ca++ elevation in response to 0.01 U/ml thrombin. MEG-01, a megakaryoblastic leukemia cell line, also responded with oscillatory intracellular Ca++ elevation (0.7-1 times/min) to thrombin (0.001-0.003U/ml). Ca++ transients appears to be fused with higher thrombin doses. With extracellular Ca++ concentrations of 0.1 mM or less, Ca++ oscillation could not be elicited, or even when present, it disappeared after a few spikings of [Ca++]i. Extracellular Ca++ concentrations of 0.3 mM or more were required to facilitate ongoing Ca++ oscillation, suggesting an important role of Ca++ influx for Ca++ oscillation.     

Ca++ regulation of paracellular permeability in the middle intestine of the eel, Anguilla anguilla

The role of Ca++ on the regulation of the paracellular pathway permeability of the middle intestine of Anguilla anguilla was studied by measuring the transepithelial resistance and the dilution potential, generated when one half of NaCl in the mucosal solution was substituted iso-osmotically with mannitol, in various experimental conditions altering extracellular and/or intracellular calcium levels. We found that removal of Ca++ in the presence of ethylene glycol-bis(beta-aminoethyl ether) (EGTA) from both the mucosal and the serosal side, but not from one side only, reduced both the transepithelial resistance and the magnitude of the dilution potential. The irreversibility of this effect suggests a destruction of the organization of the junction in the nominal absence of Ca++. However a modulatory role of extracellular Ca++ cannot be excluded. The decrease of the intracellular Ca++ activity, produced by using verapamil to block the Ca++ entry into the cell, or by adding 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester (hydrochloride) (TMB-8), an inhibitor of Ca++ release from the intracellular stores, reduced both the transepithelial resistance and the magnitude of the dilution potential, indicating a role of cytosolic Ca++ in the modulation of the paracellular permeability. However the rise of calcium activity produced by the Ca++ ionophore calcimycin (A23187) evoked an identical effect, suggesting that any change in physiological intracellular Ca++ activity alters the paracellular permeability.     

Influence of calcium and magnesium deprivation on ovulation and ovum maturation in the perfused rabbit ovary

The role of calcium (Ca++) and magnesium (Mg++) in the ovulation process was studied using in vitro perfused rabbit ovaries. Ovaries were perfused with or without human chorionic gonadotropin (hCG) in Ca++/Mg++-free medium (M199) alone or combined with standard M199 to yield varying concentrations of Ca++ and/or Mg++. In all ovaries perfused with hCG, ovulatory efficiency was similar regardless of the concentration of Ca++ and/or Mg++. In ovaries perfused in Ca++/Mg++-free medium without hCG, ovulatory efficiency was similar to that in ovaries perfused with hCG. As Ca++/Mg++ levels were increased without hCG, ovulatory efficiency declined. Ovulation time was significantly accelerated in ovaries perfused in Ca++/Mg++-free medium with or without hCG. Most ovulated ova from ovaries perfused without hCG were immature. With hCG, degree of ovum maturity was directly related to ovulation time. Ovarian smooth muscle contractions were undetectable in 3 ovaries perfused in Ca++/Mg++-free M199 despite occurrence of ovulation. Smooth muscle contractions were recorded in 2 of 3 ovaries perfused in standard M199 with hCG. These results indicate: 1) Ca++/Mg++ exclusion results in rapid follicle rupture and immature ova; 2) oocyte maturation appears to be gonadotropin-dependent; 3) ovulation occurs in the absence of ovarian smooth muscle contractions during perfusion with Ca++/Mg++-free medium.     

Anaerobic rat heart: mitochondrial role in calcium uptake and contractility.

In order to evaluate the manner by which fumarate enhances contractility in the anaerobic heart, we examined Ca++ movements in isolated heart mitochondria and in the isolated perfused heart. Our experiments showed that in isolated antimycin A plus cyanide treated mitochondria: (a) Ca++ uptake was promoted by electron transport generated by fumarate-dependent oxidation of NADH, (b) Ca++ stimulated fumarate-dependent oxidation of NADH, (c) the ratio of Ca++ uptake:NADH oxidized was 1.7 and (d) the Ca++ sequestered is transiently highly mobile and is rapidly released upon collapse of the membrane potential. In anaerobic hearts perfused with glucose plus fumarate, malate and glutamate Ca++ levels were the same as those in oxygenated hearts while in anaerobic organs perfused with or without glucose Ca++ content was appreciably lower. Succinate production in anaerobic heart perfusions was related to: (a) an increased retention of Ca++ by the heart, (b) a diminution in peak aortic pressure generated by cardiac contractions and (c) an increase in heart rate. The information obtained indicates that mitochondria have a capability for Ca++ movement which be used physiologically, particularly in fumarate perfused anaerobic hearts, to assist the mechanism for contraction and relaxation of the heart.     

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.     

The calcium dependence of pigment translocation in freshwater shrimp red ovarian chromatophores

The roles of calcium in cell signaling consequent to chromatophorotropin action and as an activator of mechanochemical transport proteins responsible for pigment granule translocation were investigated in the red ovarian chromatosomes of the freshwater shrimp Macrobrachium olfersii. Chromatosomes were perfused with known concentrations of free Ca++ (10(-3) to 10(-9) M) prepared in Mg(++)-EGTA-buffered physiological saline after selectively permeabilizing with 25 microM calcium ionophore A23187 or with 10(-8) M red pigment concentrating hormone (RPCH). The degree of pigment aggregation and the translocation velocity of the leading edges of the pigment mass were recorded in individual chromatosomes during aggregation induced by RPCH or A23187 and dispersion induced by low Ca++. Aggregation is Ca++ dependent, showing a dual extracellular and intracellular requirement. After perfusion with reduced Ca++ (10(-4) to 10(-9) M), RPCH triggers partial aggregation (approximately 65%), although the maximum translocation velocities (approximately 16.5 microns/min) and velocity profiles are unaffected. After aggregation induced at or below 10(-5) M Ca++, spontaneous pigment dispersion ensues, suggesting a Ca++ requirement for RPCH coupling to its receptor, or a concentration-dependent, Ca(++)-induced Ca(++)-release mechanism. The Ca(++)-channel blockers Mn++ (5 mM) and verapamil (50 microM) have no effect on RPCH-triggered aggregation. An intracellular Ca++ requirement for aggregation was demonstrated in chromatosomes in which the Ca++ gradient across the cell membrane was dissipated with A23187. At free [Ca++] above 10(-3) M, aggregation is complete; at 10(-4) M, aggregation is partial, followed by spontaneous dispersion; below 10(-5) M Ca++, pigments do not aggregate but disperse slightly. Aggregation velocities diminish from 11.6 +/- 1.2 microns/min at 5.5 mM Ca++ to 7.4 +/- 1.3 microns/min at 10(-4) M Ca++. Half-maximum aggregation occurs at 3.2 x 10(-5) M Ca++ and half-maximum translocation velocity at 4.8 x 10(-5) M Ca++. Pigment redispersion after 5.5 mM Ca(++)-A23187-induced aggregation is initiated by reducing extracellular Ca++: slight dispersion begins at 10(-7) M, complete dispersion being attained at 10(-9) M Ca++. Dispersion velocities increase from 0.6 +/- 0.2 to 3.1 +/- 0.5 microns/min. Half-maximum dispersion occurs at 7.6 x 10(-9) M Ca++ and half-maximum translocation velocity at 2.9 x 10(-9) M Ca++. These data reveal an extracellular and an intracellular Ca++ requirement for RPCH action, and demonstrate that the centripetal or centrifugal direction of pigment movement, the translocation velocity, and the degree of pigment aggregation or dispersion attained are calcium-dependent properties of the granule translocation apparatus.     

Attractant-induced changes and oscillations of the extracellular Ca++ concentration in suspensions of differentiating Dictyostelium cells

We used a Ca++-sensitive electrode to measure changes in extracellular Ca++ concentration in cell suspensions of Dictyostelium discoideum during differentiation and attractant stimulation. The cells maintained an external level of 3-8 microM Ca++ until the beginning of aggregation and then started to take up Ca++. The attractants, folic acid, cyclic AMP, and cyclic GMP, induced a transient uptake of Ca++ by the cells. The response was detectable within 6 s and peaked at 30 s. Half-maximal uptake occurred at 5 nM cyclic AMP or 0.2 microM folic acid, respectively. The apparent rate of uptake amounted to 2 X 10(7) Ca++ per cell per min. Following uptake, Ca++ was released by the cells with a rate of 5 X 10(6) ions per cell per min. Specificity studies indicated that the induced uptake of Ca++ was mediated by cell surface receptors. The amount of accumulated Ca++ remained constant as long as a constant stimulus was provided. No apparent adaptation occurred. The cyclic AMP-induced uptake of Ca++ increased during differentiation and was dependent on the external Ca++ concentration. Saturation was found above 10 microM external Ca++. The time course and magnitude of the attractant-induced uptake of external Ca++ agree with a role of Ca++ during contraction. During development the extracellular Ca++ level oscillated with a period of 6-11 min. The change of the extracellular Ca++ concentration during one cycle would correspond to a 30-fold change of the cellular free Ca++ concentration.     

Properties of tetraethylammonium ion-resistant K+ channels in the photoreceptor membrane of the giant barnacle

After the offset of illumination, barnacle photoreceptors undergo a large hyperpolarization that lasts seconds or minutes. We studied the mechanisms that generate this afterpotential by recording afterpotentials intracellularly from the medial photoreceptors of the giant barnacle Balanus nubilus. The afterpotential has two components with different time-courses: (a) an earlier component due to an increase in conductance to K+ that is not blocked by extracellular tetraethylammonium ion (TEA+) or 3-aminopyridine (3-AP) and (b) a later component that is sensitive to cardiac glycosides and that requires extracellular K+, suggesting that it is due to an electrogenic Na+ pump. The K+ conductance component increases in amplitude with increasing CA++ concentration and is inhibited by extracellular Co++; the Co++ inhibition can be overcome by increasing the Ca++ concentration. Thus, the K+ conductance component is Ca++ dependent. An afterpotential similar to that evoked by a brief flash of light is generated by depolarization with current in the dark and by eliciting Ca++ action potentials in the presence of TEA+ in the soma, axon, or terminal regions of the photoreceptor. The action potential undershoot is generated by an increase in conductance to K+ that is resistant to TEA+ and 3-AP and inhibited by Co++. The similarity in time-course and pharmacology of the hyperpolarization afterpotentials elicited by (a) a brief flash of light, (b) depolarization with current, and (c) an action potential indicates that Ca++-dependent K+ channels throughout the photoreceptor membrane are responsible for all three hyperpolarizing events.     

Effect of divalent metal ions on collagenase from Clostridium histolyticum.

The collagenase from Clostridium histolyticum (EC 3.4.24.3) degrades type IV collagen with Km 32 nM, indicating a high affinity for this substrate. Ferrous and ferric ions can inhibit Clostridium collagenase. Inhibition by Fe++ was of the mixed, non-competitive type, with Ki 90 microM. The inhibitory effect of Fe++ may be due to Zn++ displacement from the intrinsic functional center of this metalloprotease, since in the presence of excess amounts of Zn++ enzyme activity is retained. This inhibitory effect of Fe++ may be common for all types of collagenases, since this ion can also inhibit type IV collagenase purified from Walker 256 carcinoma, with IC50 80 microM. Cu++ can only partially inhibit Clostridium collagenase, while other divalent metal ions such as Cd++, Co++, Hg++, Mg++, Ni++ or Zn++ are devoid of any inhibitory effect on the enzyme.     

Salt stimulation of the activation of latent protein phosphatase, Fc.M, by Mn++ and by Mn/trypsin

The activation of porcine heart latent protein phosphatase (Fc.M) by pretreatment with Mn++ followed by trypsin (Mn/trypsin) can be stimulated 2.5-fold by including NaCl or KCl in the activation mixtures. The salts also stimulated the activation of the enzyme by Mn++ to the same level as that obtained by Mn/trypsin pretreatment in the absence of salt. The presence of salt in both the Mn++ and Mn/trypsin activations decreased the Mn++ requirement 10-fold in each case. Treatment of latent Fc.M by Mn/trypsin in the presence of 0.2 M NaCl or KCl offers a convenient method of expressing the full potential activity of the protein phosphatase.     

Calcium activates and inactivates a photoreceptor soma potassium current.

Light-induced currents were measured with a two-microelectrode voltage clamp of type B photoreceptor somata, which had been isolated by axotomy from all synaptic interactions as well as from all membranes capable of generating impulse activity. In artificial seawater (ASW), light elicited a transient early inward current, INa+, which depended on Na+o and had a linear current-voltage relation and an extrapolated reversal potential of 30-40 mV (absolute). In 0-Na+ ASW, light elicited a transient short-latency outward current that dependent on K+o, increased exponentially with more positive voltages (greater than or equal to -40 mV), and reversed at -70 to -75 mV. This outward current was not blocked by Ca++ channel blockers (e.g., Cd++, Co++) or substitution of Ba++o, for Ca++o, but was reduced by iontophoretic injection of EGTA. In both ASW and 0-Na+ ASW, light also elicited a delayed, apparently inward current, which was associated with a decreased conductance, depended on K+o, increased exponentially with more positive voltages (greater than or equal to -40 mV), reversed at the equilibrium potential for K+ flux in elevated K+o was eliminated by substitution of Ba++o for Ca++o, and was greatly reduced by Cd++o or Co++o. Thus, light elicited an early Ca++-dependent K+ current, IC, and a prolonged decrease of IC. Iontophoretic injection of Ca++ through a third microelectrode caused prolonged reduction of both IC and the light-induced decrease of IC, but did not alter ICa++ or the current-voltage relation of IC. Ruthenium red (1 microM) in the external medium caused a prolongation of the light-induced decrease of IC. Iontophoretic injection of EGTA often eliminated the light-induced IC decrease while decreasing peak IC (during depolarizing steps to -5 or 0 mV) by less than one-half. EGTA injection, on the average, did not affect steady state IC but reduced the light-induced decrease of steady state IC to approximately one-third of its original magnitude. The prolonged IC decrease, elicited by dim light in the absence of light-induced IC or INa+, was more completely eliminated by EGTA injection. It was concluded that light, in addition to inducing a transient inward Na+ current, causes both a transient increase and a prolonged decrease of IC via elevation of Ca++i.     

Biochemical factors involved in the FSH action on amino acid transport in immature rat testes.

Testes of 15-day-old rats preincubated and incubated during different times with various doses of FSH (0.2; 2.0 and 20.0 mU/ml) in Krebs-Ringer bicarbonate (KRb) buffer increase the uptake of [14C] methylaminoisobutyric acid and [14C] aminoisobutyric acid. The basal and FSH stimulated amino acid transport occurs at absolute lower levels when the protein or glycoprotein synthesis is inhibited by cycloheximide (350 mumol/l) or tunicamycin (12 mumol/l) or when the microtubules are depolymerized with colchicine (1.2 mumol/l). However, the proportional increase of amino acid transport produced by FSH was maintained. The blockage of the voltage-dependent Ca++ channels with verapamil or the competitive inhibition of the bivalent ion channels by Co++ or Ni++ nullified the stimulatory action of FSH on the amino acid transport. Also quinine, that blocks the ATP dependent K+ channels, abolished the FSH action. It was concluded that in immature rat testes FSH stimulates amino acid transport through a mechanism involving voltage-dependent Ca++ channels and ATP-sensitive K+ channel.     

Depolarizing response of rat parathyroid cells to divalent cations

Membrane potentials were recorded from rat parathyroid glands continuously perfused in vitro. At 1.5 mM external Ca++, the resting potential averages -73 +/- 5 mV (mean +/- SD, n = 66). On exposure to 2.5 mM Ca++, the cells depolarize reversibly to a potential of -34 +/- 8 mV (mean +/- SD). Depolarization to this value is complete in approximately 2-4 min, and repolarization on return to 1.5 mM Ca++ takes about the same time. The depolarizing action of high Ca++ is mimicked by all divalent cations tested, with the following order of effectiveness: Ca++ greater than Sr++ greater than Mg++ greater than Ba++ for alkali-earth metals, and Ca++ greater than Cd++ greater than Mn++ greater than Co++ greater than Zn++ for transition metals. Input resistance in 1.5 mM Ca++ was 24.35 +/- 14 M omega (mean +/- SD) and increased by an average factor of 2.43 +/- 0.8 after switching to 2.5 mM Ca++. The low value of input resistance suggests that cells are coupled by low-resistance junctions. The resting potential in low Ca++ is quite insensitive to removal of external Na+ or Cl-, but very sensitive to changes in external K+. Cells depolarize by 61 mV for a 10- fold increase in external K+. In high Ca++, membrane potential is less sensitive to an increase in external K+ and is unchanged by increasing K+ from 5 to 25 mM. Depolarization evoked by high Ca++ may be slowed, but is unchanged in amplitude by removal of external Na+ or Cl-. Organic (D600) and inorganic (Co++, Cd++, and Mn++) blockers of the Ca++ channels do not interfere with the electrical response to Ca++ changes. Our results show remarkable parallels to previous observations on the control of parathormone (PTH) release by Ca++. They suggest an association between membrane voltage and secretion that is very unusual: parathyroid cells secrete when fully polarized, and secrete less when depolarized. The extraordinary sensitivity of parathyroid cells to divalent cations leads us to hypothesize the existence in their membranes of a divalent cation receptor that controls membrane permeability (possibly to K+) and PTH secretion.