AMER. ZOOL., 23:719-727 (1983)
Evolution of Calcium Regulation in Lower Vertebrates'
NANCY B. CLARK
Biological Sciences Group, University of Connecticut,
Storn, Connecticut 06268
SYNOPSIS. Calcium regulation in lower vertebrates appears to be a continuum. The
predominant hypercalcemic hormone in reptiles, birds and mammals is parathyroid hormone, while the major hypercalcemic control in fishes is a puuitar) factor, probabl)
prolactin. In the amphibians dual controlling mechanisms are at work, so that both the
pituitary and parathyroids exert their influence. Prolactin may still retain some hypercalcemic potency in the higher vertebrate groups, either directly or indirectly by influencing the secretion of other hypercalcemic hormones. On the other hand, parathyroid
hormone does not occur in, nor does it elevate blood calcium in fishes. It thus seems to
be a new invention of tetrapods, or possibly to have evolved from a pituitary factor of
fishes. The ability to lower blood calcium seems to be very important in seawater fishes,
in which the corpuscles of Stannius exert major control. In terrestrial forms, the corpuscles
of Stannius are not present, and hypocalcemic factors assume a minor role in overall
calcium regulation
INTRODUCTION
Calcium ions function in myriads of cell
processes and biochemical pathways, and
regulation of their concentration must be
fairly precise. The regulation of calcium
ions in vertebrates involves a number of
hormones that act upon diverse target
organs. This topic has been the subject of
several recent reviews (Pang el al., 1980/>:
Pang and Yee, 1980: Feinblatt, 1982). Thus
it is well known that parathyroid hormone
acts upon targets such as kidney and bone
to elevate circulating levels of calcium in
tetrapods. In fishes, the major regulation
of calcium appears to involve hormones
from the pituitary and Stannius corpuscles
that act via the gills and possibly other targets. While there is much evidence for the
importance of vitamin D metabolites in calcium regulation in birds and mammals, and
some evidence for a role of calcitonin,
unfortunately little is known at present
about their function in the lower vertebrates. Thus I have not devoted much
attention to either of these hormones in
this review.
It is the purpose of this paper to explore
some of the ways in which various verte' From the Symposium on Evolution of Endocrine
Systems in Lower Vertebrates, A Symposium Honoring Pro-
fessor Aubrey Gorbman presented at the Annual Meeting of the American Society of Zoologists, 27-30
December 1982, at Louisville, Kentucky.
brates are thought to maintain calcium balance, and to speculate on how regulation
of calcium has evolved in vertebrates. I will
begin by reviewing briefly current thoughts
about the regulation of calcium in fishes.
The changes that occur in this regulation
in amphibians coincident with adaptation
to a terrestrial environment will then be
considered. This is a most interesting point
in time in which new hormones and target
organs seem to have been recruited. Finally,
I would like to consider possible evolutionary changes in the structure and function
of the parathyroid gland and its hormone,
as well as evolutionary changes that may
have occurred in its major targets as one
ascends the vertebrate tree. These may
offer some clues relative to the refinement
of calcium regulation in "higher" forms.
Of course one can speculate about evolutionary changes in physiological parameters only in terms of what we know about
present-day organisms and the structure
and function of their hormones and targets. As stated by Nicoll (1980), we have
to make inferences about our ancestral vertebrates on the basis of what is known about
a few animals that are now occupying the
"twigs of the evolutionary tree." Thus it
is important to keep in mind that the conclusions reached in this paper are probablybased upon biased sampling and incomplete information, and are completely
presumptuous.
719
720
NANCY B. CLARK
Similanlyof Amino Acid Sequence in
ACTH and Parathyroid Hormone
ACTH 1-11 N H 2 - s e r - l y r -
met- glu- his-phe-argttrp.gly - l y s -
BOVINE 15-25
met- -glu arg -val - gln-j-trp - leu-arg-
teu-ser-
Fic. 1. Similarities in portions of the ACTH and
PTH molecules. Identical portions are enclosed in
rectangles.
CALCIUM REGULATION IN FISHES
Many hormones have been suggested to
function in calcium regulation in fishes.
One of them, a hypocalcemic factor from
the corpuscles of Stannius, appears to be
unique to fishes, and there is good experimental evidence of its involvement in calcium regulation. Others, such as calcitonin
and vitamin D metabolites, have been
implicated in teleost calcium regulation
because of their effects in higher vertebrates and the fact that they are known to
be present in fishes. Evidence for their
involvement in calcium regulation in fishes
is limited, however, either from lack of positive data, or lack of sufficient studies. Parathyroid hormone has been tested as a calcium-regulating factor in fishes, despite the
fact that parathyroid glands are not present in this vertebrate class. There is little
evidence that it plays any role in teleost
calcium regulation. Finally, a pituitary factor, termed "hypercalcin," has been implicated.
There is good evidence for pituitary
involvement in elevation of calcium concentrations in fishes. For example,
hypophysectomized fish kept in seawater
show no ill effects, but if they are transferred to calcium-deficient seawater they
become severely hypocalcemic and
undergo tetanic convulsions (Pang et ai,
1971). Pituitary transplants or pituitary
homogenates will restore normal blood
calcium values. Prolactin has been suggested as the hormone responsible for these
effects. Exogenous prolactin is hypercalcemic in fish at very low doses and its
hypercalcemic effect is dose-dependent
(Pang et ai, 1978). On the basis of morphological studies, it has been suggested
that prolactin is secreted in fish in response
to alterations of plasma calcium levels
(Wendelaar Bonga, 1978; Wendelaar
Bonga et ai, 1978, 1980). However, other
studies have indicated no such link (Nicoll
et ai, 1981; Grau et ai, 1981). Rather,
secretion of prolactin was linked to the
osmolality of the body fluids.
On the other hand, prolactin takes a long
time to elevate blood calcium (two days;
Bern etai, 1981), and this has raised doubts
that it is the major physiological factor for
hypercalcemic regulation in fish. Immunological studies conducted by Parsons et
ai (1978) of fish pituitaries indicated the
presence of a factor that was similar to
parathyroid hormone. They have pointed
out structural similarities between the
sequence of several amino acids in the 111 fragment of the ACTH molecule and
amino acids 15-25 (part of the active fragment) of bovine parathyroid hormone (Fig.
1). While ACTH and cortisol cause hypercalcemia in fishes, mammalian parathyroid
hormone itself does not. The hypothesis
that hypercalcin is ACTH is an interesting
one, since it would suggest evolution of the
structure of a hypercalcemic hormone
throughout the vertebrates, rather than a
shift from use of one hormone to another
in order to raise blood calcium values in
different vertebrate classes. However, this
work needs confirmation and extension.
Other experiments by Ball et ai (1982)
suggest that there may be a hypercalcemic
factor from the pars intermedia of the fish
pituitary. They placed killifish in calcium
deficient seawater, causing hypocalcemia,
and then studied the pituitary for any histological changes. They found striking
enlargement and activation of certain cells
of the pars intermedia that are PAS positive (PIPAS cells). Interestingly, the prolactin cells of the pars distalis were only
minimally affected and other cell types did
not change at all. This work may indicate
the presence of a second hypercalcemic
hormone from the fish pituitary.
The ability offish to reduce their blood
calcium levels may also involve hormonal
control by one or more hormones. There
is good evidence for a physiological calcium-lowering hormone from the Stannius
corpuscles in fishes. Remo\al of the glands
721
CALCIUM REGULATION IN LOWER VERTEBRATES
results in a prolonged hypercalcemia that
is reversed by corpuscle transplants or
homogenates (see review by Feinblatt,
1982). One substance, termed teleocalcin,
has been shown to be a glycopeptide with
a molecular weight of about 3,000. It
appears to function in blocking calcium
uptake across the fish gill by inhibiting the
calcium-dependent ATPase (Copp and Ma,
1981; Fig. 2). Pangea/. (1974) previously
described a hypocalcemic Stannius corpuscle factor, hypocalcin, that contains reninlike activity. They suggested (Pang et al.,
1981) that hypocalcin may catalyze the
production of an angiotensin-like plasma
factor which is hypocalcemic in the killifish
assay. Recent work by Milet et al. (1982)
and Lopez et al. (1982) suggests that in the
Stannius corpuscles of the eel there is a
hypocalcemic hormone that resembles
mammalian parathyroid hormone. This
substance, called "parathyrin," may prove
to be another link to calcium regulation in
the tetrapods. Clearly more work needs to
be done to resolve the number and chemical nature of hypocalcemic factors in the
Stannius corpuscles.
Although calcitonin is present in large
amounts in the piscine ultimobranchial
gland, it has been difficult to show its
importance in calcium regulation. The
secretion of calcitonin by fish ultimobranchial glands appears to be stimulated by
hypercalcemia; however removal of the
ultimobranchial glands or administration
of exogenous calcitonin have either
resulted in no significant changes, or at
best about a 10% change in serum calcium
values (see review by Feinblatt, 1982). Fenwick (1978) has suggested that the ultimobranchial body acts along with the Stannius corpuscles in decreasing blood calcium
in eels. Since the fish may have two systems
for reducing blood calcium, the effect of
calcitonin may not be apparent until the
Stannius corpuscles are removed or are not
functional. Removal of both the Stannius
corpuscles and the ultimobranchial glands
resulted in significant hypercalcemia and
increased renal excretion of calcium in the
eels.
It is probable that in a given fish, which
is exclusively freshwater or marine, only
X 110 0 -
1
E
5 0 -
8
Is
t
SO
120
160
200
240
Time in Minutes
74xl
FIG. 2. Effect of removal of the Stannius corpuscles
(STX) and administration of teleocalcin on calcium
uptake by the isolated eel gill. (From Copp and Ma,
1981)
one of the calcium-regulating hormonal
systems is used. Thus, if the problem is that
too much calcium is available, as in the
seawater environment, the hypocalcemic
hormones are of major importance. Freshwater fish, on the other hand, need to
obtain calcium from a deficient environment, and thus the hypercalcemic hormones predominate. Except perhaps in
euryhaline fish, or those that migrate
between fresh and saltwater, it is doubtful
if there is control of calcium by both hypercalcemic and hypocalcemic hormones.
CALCIUM REGULATION IN AMPHIBIANS
The amphibians appear to be a point of
divergence from the systems of calcium
regulation in fish. The corpuscles of Stannius are not found in tetrapods, and a role
for calcitonin is uncertain. Robertson
(1969a, b) reported that removal of the
ultimobranchial glands in Rana pipiens
results in transient hypercalcemia and
increased urinary calcium excretion. However, in other studies, he was unable to
demonstrate any hypocalcemic effect of the
ultimobranchial glands in the absence of
the parathyroid glands (Robertson, 1977).
These studies are complicated by the
occurrence of seasonal cyclic changes in
blood calcium values in this species. It is
uncertain at present if there is a major calcium-lowering hormone in amphibians.
Parathyroid hormone is considered to be
722
NANCY B. CLARK
the major calcium-elevating hormone in
amphibians. While the parathyroid gland
first appears in amphibians, this is not a
universal event. In some urodeles, the
parathyroids appear at the time of metamorphosis, and in some neotenous salamanders, such as the mudpuppy (Xecturus),
the parathyroid glands never appear at all.
In these groups, it is clear that they have
retained the fish-like pattern of being able
to maintain blood calcium values with a
pituitary hypercalcemic factor (Oguro,
1973; Pang, 1981). In some other salamanders, in which the parathyroid glands
are present, parathyroidectomy has either
a transient or no effect upon blood calcium
values, and again the pituitary appears to
dominate in this control. In still other
forms, parathyroidectomy results in significant hypocalcemia while hypophysectomy does not affect blood calcium values.
Thus there appear to be two different
methods by which urodele amphibians elevate their plasma calcium values. To simplify the situation, the more primitive and
aquatic forms seem to be those in which
the pituitary factor is dominant, while the
parathyroid seems to be dominant in the
more advanced and terrestrial groups (Pang
etal, 19806).
The parathyroid gland is present in all
anuran groups, including the larval forms.
The parathyroid gland seems predominant
in regulating blood calcium values in
anurans, but even here there is evidence
of some pituitary involvement. For example, Uchiyama and Pang (1982) and Sasayama and Oguro (1975) have implicated
both the parathyroids and pituitary in calcium regulation in tadpoles. Either parathyroidectomy or hypophysectomy result
in hypocalcemia, and either parathyroid
hormone or prolactin will elevate plasma
calcium levels. It has been suggested (Pang
and Yee, 1980) that the pituitary is important in maintenance of blood calcium in
aquatic vertebrates. It may be that it is still
of some importance in some terrestrial
forms as well. For example, parathyroidectomy of adult anurans results in hypocalcemia, the effect t\pical of most tetrapods. However, after a period of time, the
blood calcium values return to normal
(Cortelyou et ah, 1960; Houston and Husbands, 1965). While the recovery from
parathyroidectomy may be due simply to
recruitment of accessory parathyroid tissue, it may also be the result of another
hypercalcemic factor replacing parathyroid hormone. Thus it might be of interest
to explore the effect of hypophysectomy
upon calcium values in adult anurans.
Interestingly, the structure of the parathyroid gland is variable in amphibians. In
anurans, the gland consists of whorls of
cells very unlike parathyroid structure in
the other tetrapod groups (Fig. 3). Additionally, the gland undergoes seasonal
degeneration. There is reported to be a
seasonal fluctuation in plasma calcium values in anurans (Robertson, 1977), but this
does not seem to correlate well with the
histological appearance of the parathyroid
gland (Cortelyou, 1960; von Brehm, 1964).
One might expect that the parathyroid
structure of urodeles might vary widely,
and in some cases be very unlike that of
higher vertebrates, but this is not the case.
In fact, the structure of the parathyroids
is very similar to that of higher vertebrates.
Studies undertaken to show seasonal variation in the parathyroid glands of salamanders have been unsuccessful (Wittle
and Dent, 1979). This is rather puzzling in
light of physiological studies. Some examples of the variation in amphibian parathyroid structure are shown in Figure 3.
HYPERCALCEMIC REGULATION IN
REPTILES, BIRDS AND MAMMALS
The structure of the parathyroid glands
in reptiles, birds and mammals is very similar. In some groups, such as turtles, the
glands contain follicles of unknown function, but otherwise the parathyroid gland
consists of characteristic cell cords. Also in
all these groups (except, perhaps, some
species of turtles), parathyroidectomy
results in severe hypocalcemia, tetany and
death. Parathyroid regulation of calcium
is dominant in these groups, and there
seems no reason to suspect that there is
additional control by a pituitary factor.
However, it may be of interest to investigate the role of prolactin in calcium regulation in these groups. Prolactin has been
CALCIUM REGULATION IN LOWER VERTEBRATES
723
FIG. 3. Histology of the parathyroid glands of amphibians. A. Adult frog parathyroid Rana pipiens. Capillaries
are limited mainly to the subcapsular region of the gland (arrows). X200. B. Detail of frog parathyroid showing
spindle-shaped cells arranged in whorls in the summer frog. X860. C. Parathyroid gland of the red spotted
newt, Notophthalmus viridescens. Capillaries run between the cell cords (arrows). D. Detail of newt parathyroid,
showing the cell cord structure of the gland. A and B from Cortelyou et al., 1960. C and D from Wittle and
Dent, 1979.
reported to stimulate the secretion of parathyroid hormone and the production of
1,25-dihydroxyvitamin D3 by the kidney
in mammals (Pahuja and DeLuca, 1981;
Magliola et al., 1981). As in amphibians,
there seems to be no major role played by
a hypocalcemic hormone, such as calcitonin.
Birds and mammals seem to be able to
regulate their blood calcium concentrations more precisely than reptiles. It seems
likely that this relates to differences in the
response of the target organs to variations
in circulating levels of parathyroid hormone. For example, studies in our laboratory indicate that the renal tubules of
some birds (chicken, quail, starling), like
mammals, reabsorb most of the calcium
filtered at the glomerulus when parathyroid hormone is present. In the absence of
the hormone, however, excessive amounts
of calcium are lost in the urine (Clark and
Wideman, 1977; Clark and Sasayama,
1981; Fig. 4A). However, this ability to
724
NANCY B. CLARK
|
Pattern for all Tetrapods
Avian and Mammalian Pattern
E3 Reptilian and Amphibian Pattern
l.5r
0.3r
0.2
o
o
0.1
INTACT
PTX
PTX+PTH
INTACT
PTX
PTX+PTH
FIG. 4. Patterns of renal clearances of calcium and phosphate in various vertebrate groups in relation to
parathyroid hormone status. A. The fractional excretion of calcium (Cc^/C.J is not parathyroid hormone
dependent in amphibians and reptiles (hatched bars), as it remains essentially the same in intact, parathyroidectomized (PTX) and parathyroid hormone (PTH) treated animals. However, in birds and mammals, excessive
calcium is lost via the kidney following PTX. B. The fractional excretion of phosphate (CPO4/C,n) is parathyroid
hormone dependent in all tetrapods. Parathyroidectomy reduces the urinary loss of phosphate (sometimes to
zero) and parathyroid hormone administration restores the ability of the tubules to excrete (or secrete)
phosphate.
conserve calcium at the level of the renal
tubule in response to parathyroid hormone
is not seen in reptiles (Clark and Dantzler,
1972; Laverty and Clark, 1981). Interestingly, it is also absent in frogs (Sasayama
and Clark, unpublished; Fig. 4A). It is possible that changes in the structure of the
target organ, or the location of the receptor molecules to the hormone, may be of
paramount importance in determining the
function of a hormone. Figure 5 serves to
remind us of the profound structural
changes that occur in the renal tubule of
vertebrates. The ability of the tetrapod
kidney tubule to excrete filtered phosphate
is also parathyroid hormone dependent.
After parathyroidectomy, phosphate
excretion falls to near zero. Restoration of
parathyroid hormone will result in
increased renal phosphate excretion, and
in some cases phosphate secretion will
occur. This pattern of phosphate excretion
is the same in all tetrapods (Fig. 4B).
The processing of urine once it leaves
the renal tubule also varies in tetrapods.
For example, the urinary bladder of
amphibia and the cloaca of reptiles and
birds may function as sites of reabsorption
of calcium (Bentley, 1966; Skadhauge,
1977). We have measured calcium values
in ureteral urine of Rana pipiens as high as
40% of what was filtered (Sasayama and
Clark, unpublished). This would mean that
there is a large loss of calcium in the urine
unless it were subsequently reabsorbed in
bladder or cloaca. Since amphibians live in
a calcium-poor environment, we would
expect a calcium-conserving mechanism to
be in operation.
Skadhauge (1977) has reviewed his studies that indicate that considerable amounts
of water and ions are reabsorbed across the
cloaca and terminal gut membranes in representatives of birds, reptiles, amphibians
and fishes and has established this as an
important site in water and mineral regulation. Although these studies emphasize
water and sodium chloride reabsorption,
it is possible that calcium could also be
reabsorbed at these sites. Hormones implicated in the reabsorption of sodium chloride and water from these storage organs
CALCIUM REGULATION IN LOWER VERTEBRATES
725
Frc. 5. Evolution of the structure of the vertebrate kidney tubule, in relation to a saltwater (darkly shaded)
and freshwater (lightly shaded) habitat. From H. W. Smith, 1961, From Fish to Philosopher. Little Brown &
Co., Boston.
include aldosterone, arginine vasotocin,
cortisol and, in freshwater fish, prolactin.
One further topic that should be mentioned is the change in another of the possible targets of calcium-regulating hormones in vertebrates, the bones. There
seems to be little written regarding the
comparative physiology of this organ system (Urist, 1976; Simmons, 1976). However, it is clear that bone seems to be of
little importance in calcium homeostasis in
fishes. The skeleton contributes little to the
turnover of calcium and phosphate (Urist,
1976). In fact, Pang et al. (1980«) have
pointed out that environmental water
rather than bone may be an important reservoir of calcium for freshwater fish. In
other vertebrate groups, bones may act as
important storage sites of calcium and
recovery of stored calcium and phosphate
could occur rapidly across the bone surfaces or in longterm response to osteoclast
activity. Even in these groups the skeleton
may not normally function in the minuteto-minute regulation of blood calcium, but
can be called upon in times of long-term
need. Podbesek etal. (1981) have provided
evidence that parathyroid hormone is ana-
bolic when administered in small, physiological doses, and thus the hormone may
play a role in bone production as well as
in bone breakdown. One case in which bone
is mobilized to provide a quick source of
calcium is the breakdown of medullary
bone in laying birds. The hormonal control of this impressive mechanism in which
calcium is moved from blood to bone to
shell gland is not yet clear.
Thus in reptiles, birds and mammals, calcium homeostasis appears to be under the
primary control of parathyroid hormone.
This is secreted in response to hypocalcemia and elevates blood calcium values by
way of reabsorption of calcium at the level
of the kidney and probably also by releasing calcium from bone. Hypocalcemic factors appear to play a minor role in this
regulation.
ACKNOWLEDGMENTS
I wish to acknowledge my mentor,
Aubrey Gorbman, who suggested that
comparative studies of calcium regulation
would be a fascinating area of study. This
work was supported by grant 81-04037
from the National Science Foundation.
726
NANCY B. CLARK
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