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MICROSCOPY RESEARCH AND TECHNIQUE 40:479–487 (1998)
Intracellular Distribution of Adenylate Cyclase in Human
Cardiocytes Determined by Electron Microscopic
Cytochemistry
SHOJI YAMAMOTO,1 KEISHIRO KAWAMURA,2 AND THOMAS N. JAMES1*
1World
Health Organization Cardiovascular Center and the Department of Medicine and Department of Pathology
at the University of Texas Medical Branch, Galveston, Texas, USA
2Osaka Medical College, Osaka, Japan
KEY WORDS
sarcoplasmic reticulum; nuclear envelope; intracellular compartmentalization
ABSTRACT
Subcellular localization of adenylate cyclase (AC) in human cardiocytes was
studied by electron microscopic cytochemistry using ventricular biopsies from various diseased
hearts. In addition to the weak enzyme activity on the sarcolemma, the intense reaction products of
AC were demonstrated within distinctive morphologic components of sarcoplasmic reticulum,
nuclear envelope, and other internal membranes such as parallel lamellar structures and interlaced
tubular structures in the perinuclear regions and stacked membranous structures beneath
sarcolemma in cardiocytes. The distribution and intensity of cytochemical activity within different
organelles was variable among biopsy cases. The reaction products of AC cytochemistry within the
sarcoplasmic reticulum could be related to signal transduction targeting Ca21 handling by the
organella. Cytochemical activity within the nuclear envelope and perinuclear internal membranes
possibly reflects AC participation in a signal function to regulate nuclear activity, such as gene
expression. Cytochemical distribution of the enzyme in membranous structures beneath the
sarcolemma is most likely related to hormone receptors and the linked activity of AC. The
subcellular distribution of AC on various internal membrane structures in cardiocytes may reflect
compartmentalization of the enzyme at individual intracellular sites to regulate a preferential
specific signal function among multiple potential signal transductions by a cascade of AC, cyclic
AMP, and cyclic AMP-dependent protein kinase. Alternatively, subcellular localization of the
reaction products may reflect local enzyme synthesis or represent sites of enzyme transport, e.g., to
terminal localization beneath the sarcolemma. Microsc. Res. Tech. 40:479–487, 1998. r 1998 Wiley-Liss, Inc.
INTRODUCTION
Cytochemical studies have demonstrated intracellular adenylate cyclase (AC) activity within the sarcoplasmic reticulum or beneath the sarcolemma in animal
(Revis, 1979; Schulze et al., 1972; Slezak and Geller,
1979, 1984; Wollenberger and Schulze, 1976) and human (Yamamoto et al., 1991) cardiocytes. Despite various attempts to improve cytochemical methods (Cutler,
1975; Howell and Whitfield, 1972; Schulze et al., 1977;
Schulze, 1982; Slezak and Geller, 1979; Wagner et al.,
1972), there are still some questions about the reliability of AC cytochemistry (Kempen et al., 1978; Lemay
and Jarett, 1975; Richards, 1994; Schulze, 1982). Nevertheless, electron microscopic cytochemistry has become
both the most sensitive and the most widely used
method to demonstrate a subcellular distribution of AC
(Richards, 1994).
Recently, cloning of cDNAs has identified a family of
at least eight mammalian AC isoforms which differ in
their amino acid sequence, tissue distribution, and
regulatory features of enzyme activity, including response to Ca21.They also differ in chromosomal location
of coding genes (Espinasse et al., 1995; Gaudin et al.,
1994; Haber et al., 1994; Iyengar, 1993). Among the
different isoenzymes, type V and VI are the major AC
isozymes expressed in mammalian heart (Espinasse et
r 1998 WILEY-LISS, INC.
al., 1995; Katsushika et al., 1992; Yu et al., 1995). By
means of an antiserum that recognizes a peptide sequence shared by all known mammalian AC isoforms,
studies with immunohistochemistry by electron microscopy have demonstrated in nerve cells a selective
subcellular distribution of AC protein in the cytosol and
certain internal membranes (Mons et al., 1995). As
more sensitive methods are now available for the
demonstration of AC localization, the credibility of the
subcellular distribution of AC has increased.
AC, along with cyclic AMP (cAMP) and cAMPdependent protein kinase, mediates a signal transduction which regulates a variety of physiological responses by cells. To control a specific signal function
among multiple potential signal transductions, compartmentalization of cAMP and cAMP-dependent protein
kinase has been suggested as a regulatory mechanism
(Coghlan et al., 1993; Hausken et al., 1994; McCartney
et al., 1995; Oquist et al., 1992; Smith et al., 1993;
Yabana et al., 1995). In the present study, we demon-
Contract grant sponsor: Pegasus Fund of the University of Texas Medical
Branch, Galveston, Texas.
*Correspondence to: Thomas N. James, M.D., Office of the President, University of Texas Medical Branch, Galveston, Texas 77555-0129 USA.
Received 30 July 1996; accepted in revised form 13 November 1996.
480
S. YAMAMOTO ET AL.
Fig. 1. Electron microscopic cytochemistry of AC in a left ventricular myocardial biopsy. AC activity is demonstrated as electron-dense
deposits of reaction products on well-preserved fine structures of a
cardiocyte. In addition to the weak activity within sarcolemma, the
intense activity is seen in association with various intracellular
organelles (arrowheads). More details of AC activity in boxed areas (A,
B, and C) are shown in Figures 2 and 3. All micrographs are electron
microscopic cytochemistry of AC and stained with uranyl acetate
and/or lead citrate.
strate cytochemical localization of AC at several different intracellular sites in addition to the sarcoplasmic
reticulum and sarcolemma in human cardiocytes.
cytochemical study to demonstrate AC activity (Slezak
and Geller, 1979, 1984).
Immediately after biopsy, tissues were fixed for 15
minutes at 4°C with 2% paraformaldehyde and 0.25%
glutaraldehyde in 0.1 mol/L sodium cacodylate buffer
(pH 7.4) containing 8% sucrose and 5% DMSO. Tissues
of sufficient size were cut with a Vibratome (Technical
Products International, St. Louis, MO) into 40 µm thick
sections to facilitate diffuse infiltration of the tissues
with incubation medium. Smaller tissues were treated
as a block. After fixation, tissues were rinsed in the
same buffer for 1 to 2 hours at 4°C. Incubation in freshly
prepared medium was for 45 minutes at 37°C to
demonstrate AC activity. The assay medium consisted
of 80 mmol/L Tris-maleate buffer (Sigma Chemical, St.
Louis, MO), pH 7.4, with 8% sucrose, 5% DMSO, 2
mmol/L theophylline (Nakarai, Kyoto, Japan), 4 mmol/L
MgSO4 (Nakarai), 2 mmol/L lead nitrate as tracer, and
purified 0.5 mmol/L adenylate imidodiphosphate (AMPPNP; Sigma) as substrate. Then 20 mmol/L NaF (Nakarai) and 10 mmol/L DL-isoproterenol HCl (Nakarai)
were added as activators of AC. In some controls,
ouabain (G-strophanthin; Nakarai) 10 mmol/L was
added as an inhibitor of (Na1, K1)ATPase, and 1
MATERIALS AND METHODS
Materials
Sixteen myocardial biopsies (six from the right ventricle and ten from the left ventricle) were obtained
from 16 patients by means of a Konno-Sakakibara
bioptome (Sakakibara and Konno, 1962; Konno and
Sakakibara, 1963) at catheterization or by Vim Silverman needle during open-heart surgery or permanent
pacemaker implantation. The patients included 14 men
and two women, age 34 to 63 years (mean, 49); seven
patients had congenital or acquired heart diseases and
nine had idiopathic cardiomyopathies (five cases dilated and four hypertrophic). Informed consent for
biopsy was obtained from every patient and all procedures were conducted according to the principles of the
Declaration of Helsinki.
Methods
In addition to conventional light and electron microscopy studies, parts of each biopsy sample served for
AC DISTRIBUTION IN CARDIOCYTES
481
Fig. 2. Higher magnification of boxed areas A (2a) and B (2b) from
Figure 1. (a) The reaction products of AC are seen within tubular
elements of sarcoplasmic reticulum associated with myofibrils (arrows) and cobular element of sarcoplasmic reticulum (arrow heads).
(b) The reaction products are seen within internal (arrows) and
peripheral (arrow heads) junctional sarcoplasmic reticulum. Reference bars 5 1 µm. Mf, myofibril; T, T tubule: IS, interstitial space.
mmol/L levamisole HCl (Aldrich Chemical., Milwaukee, WI) was added as an inhibitor of alkaline phosphatase in the assay medium. Tissues for cytochemical
control were incubated in the medium without AMPPNP. After incubation, tissues were rinsed several
times in 0.1 mol/L sodium cacodylate buffer (pH 7.4)
containing 8% sucrose and postfixed for 10 minutes at
4°C with 1% osmium tetroxide in 0.1 mol/L sodium
cacodylate buffer (pH 7.4). Serial dehydration in graded
alcohols and propylene oxide was followed by embedding in Epon resin (Luft, 1961).
Semithin (1 µm) sections were cut with an LKB 8800
Ultratome III and stained with toluidine blue to use for
selection purpose. Ultrathin sections were cut with a
diamond knife, stained with aqueous uranyl acetate
and/or lead citrate, and examined with either a Hitachi
300 or H-7000 electron microscope.
intracellular organelles (Figs. 1–7). In controls in which
tissues were incubated in the assay medium with
ouabain and levamisol HCL, lesser amounts of nonspecific dispersion of deposits were seen. However, there
was no difference in the enzyme localization in association with specific intracellular structures. No reaction
products of the enzyme activity were seen in tissues of
the cytochemical controls.
Weak activity of AC, seen as spotty or uneven distribution of small amounts of reaction deposits, was found
in association with sarcolemma in most biopsy specimens. However, intense enzyme activity with homogenous or dense distribution of abundant deposits was
demonstrated only on different intracellular organelles.
The intensity and distribution of the cytochemical
enzyme activity on individual organelles differed among
biopsy specimens but had no apparent correlation with
the clinical diagnosis.
The most frequently observed localizations of AC
cytochemical activity were in the sarcoplasmic reticulum, nuclear envelope, perinuclear lamellar and tubular structures, and subsarcolemmal membranous structures.
RESULTS
AC activity was apparent as deposits of coarse or fine
granules of electron-dense reaction product. Fine structures of tissues were well preserved so that a localization of the enzyme could be studied in relation to
482
S. YAMAMOTO ET AL.
Fig. 3. Higher magnification of boxed area C from Figure 1. The
cytochemical activity is demonstrated in association with parallel
lamellar structures in the perinuclear region (arrows). The cisternae
are stacked in parallel with narrow cytoplasmic interspaces. The
reaction products are seen within individual cistern structures. The
enzyme activity is also seen within tubular structures near the
nucleus (arrow heads). Reference bar 5 1 µm. N, nucleus; Lf,
lipofuscin granule.
Sarcoplasmic Reticulum
AC activity was present in several morphologically
distinct components of sarcoplasmic reticulum (Fig. 2).
The reaction products were seen on both the internal
and peripheral junctional sarcoplasmic reticulum in
many cardiocytes of most biopsy specimens. In some
specimens, the enzyme activity was localized on additional tubular elements of free sarcoplasmic reticulum
associated with myofibrils and mitochondria. Reaction
products were also seen on corbular elements of sarcoplasmic reticulum. The localization patterns of the
enzyme activity among the different components of
sarcoplasmic reticulum were variable among individual cardiocytes.
Perinuclear Parallel Cisternae and Interlaced
Tubular Structures
In some biopsy specimens, the enzyme activity was
present in parallel lamellar structures in the peri-
Fig. 4. Electron micrograph of a right ventricular myocardial
biopsy. The enzyme activity is localized within tubular structures
(arrows) which present an interlaced network in the perinuclear
region of a cardiocyte. The tubular structures appeared to be endoplasmic reticulum, even though not clear whether rough or smooth
components of the reticulum. Reference bar 5 1 µm.
nuclear regions (Fig. 3). The membrane structures
consisted of stacks of parallel cisternae. The reaction
product was most intense in individual cisternae. In the
perinuclear regions of some cardiocytes, the enzyme
activity was also demonstrated in association with
interlaced tubular structures (Fig. 4).
Nuclear Envelope
AC activity was demonstrated on nuclear envelope in
some cardiocytes (Fig. 5). These reaction products were
found mainly in association with the perinuclear cisterna, a space between the two parallel (outer and
inner) membranes of the nuclear envelope.
Membranous Structures at the Cell Periphery
Enzyme activity was occasionally demonstrated in
association with membranous structures at the cell
periphery (Fig. 6). A few membranous structures be-
AC DISTRIBUTION IN CARDIOCYTES
Fig. 5. Electron micrograph of a right ventricular myocardial
biopsy. AC activity is demonstrated in the nuclear envelope (arrows).
The reaction products are localized within the perinuclear cisternae of
the envelope. The enzyme activity is also seen in association with the
parallel lamellar structures (arrowheads). Reference bar 5 1 µm. Mt,
mitochondria.
neath the sarcolemma were stacked in parallel with
narrow cytoplasmic interspaces. The reaction products
were localized on individual membranes. The membranous structures were flattened cisternae with two
membranes opposed tightly. Coated vesicles and endocytotic pits were occasionally seen in the same vicinity.
Other Organelles
Additional intracellular organelles in which enzyme
activity was demonstrated (Fig. 7) included vesicular,
tubular, and membranous structures of undetermined
origin or derivation.
DISCUSSION
Intracellular Localization of AC in Cardiocytes
Cytochemical demonstration of AC activity has often
been done in various mammalian tissues, including
heart. Questions about the validity of cytochemistry
have been based upon several criticisms of histochemical procedures such as substrate specificity, nonenzymatic hydrolysis of AMP-PNP by lead, and inhibition of AC activity by lead or by fixation procedures
(Kempen et al., 1978; Lemay and Jarett, 1975; Rich-
483
ards, 1994; Schulze, 1982). Various methodologic improvements have been developed in response to this
criticism (Cutler, 1975; Howell and Whitfield, 1972;
Schulze et al., 1977; Slezak and Geller, 1979; Wagner et
al., 1972) and quantitative analysis of the effect of
individual cytochemical procedures on AC has been
studied in different tissues, including heart (Schulze,
1982). Detailed efforts to standardize optimal procedures among many improved cytochemical methods
were also conducted in animal tissues, such as epidermal epithelium (Richards, 1994).
In the present study, methodologic improvements
included the use of AMP-PNP as substrate, ouabain
and levamisol HCl as other enzyme inhibitors, and low
lead concentration of tracer. Considering the possible
inhibition of basal activity of AC by lead (Schulze, 1982)
and the stimulation of the enzyme activity by isoproterenol and NaF in the incubation medium in the present
study, the localization of AC presented here could be
associated with hormone-stimulated enzyme activity,
not solely with the basal enzyme activity. The localization of AC activity we found in human cardiocytes is
consistent with the cytochemical distribution of the
enzyme in other mammalian cardiocytes (Schulze et al.,
1972, 1977; Slezak and Geller, 1979, 1984; Wollenberger and Schulze, 1976). As we previously reported
using similar biopsy materials of human myocardium
(Yamamoto et al., 1991), AC was again cytochemically
demonstrated within sarcoplasmic reticulum in addition to weak enzyme activity on sarcolemma. But we
have now demonstrated the intracellular distribution
of enzyme activity in association with a wide spectrum
of other membrane structures. The cytochemical distribution of AC among intracellular organelles was variable among biopsy cases, irrespective of their clinical
diagnosis. The cytochemical variations could reflect
intrinsic involvement of the AC system in diseased
cardiocytes, but also the various alterations of enzyme
activity in response to multiple extrinsic regulation on
cardiocyte functions.
Even with the methodologic improvements used in
the present study, the results may not be totally free of
the problems of cytochemical procedures. For example,
the validity of the distribution of enzyme activity on
internal membranes is still controversial (Richards,
1994). Sarcoplasmic reticulum, which exhibited the
most intense enzyme activity in the present study, is
known as the crucial regulatory site of cytosolic Ca21,
which is a principal target of hormonal signal transduction in cardiocytes. The localization of other mediators
such as cAMP and cAMP-dependent protein kinase on
sarcoplasmic reticulum has already been suggested
(Coghlan et al., 1993; Hausken et al., 1994; McCartney
et al., 1995; Oquist et al., 1992; Smith et al., 1993;
Yabana et al., 1995). Thus, we believe that the cytochemical localization within sarcoplasmic reticulum
and other internal membranes in the present study is
closely related to subcellular distribution of in vivo
activity of AC.
Cyclic AMP has been long recognized as a second
messenger (Gilman, 1987; Pastan, 1972; Schramm and
Selinger, 1984; Sutherland, 1972). The cytochemical
localization of AC on cell membranes is consistent with
the enzyme distribution linked with hormone receptors
on cell membranes. Conversely, the cytochemical local-
484
S. YAMAMOTO ET AL.
Fig. 6. Electron micrographs of a left ventricular biopsy. AC
activity is present within membranous structures at the cell periphery
(arrows). Those beneath the sarcolemma are stacked in parallel with
narrow cytoplasmic interspaces. Insert is electron micrograph from a
different serial ultrathin section of the same cardiocytic area. Similar
structures presented at different levels in these serial sections indicate
that the enzyme activity is present in membranous structures situated
parallel to the sarcolemma. Coated vesicle (large arrowhead) and
coated pit (small arrowhead) are seen in the vicinity of enzyme
localization. Reference bars 5 1 µm.
ization of AC within intracellular organelles might be
questioned on the basis of inconsistency with the
second-messenger theory. In a recent immunohistochemical study of AC in nerve cells (Mons et al., 1995),
some reaction products were detectable in association
with endoplasmic reticulum or microtubules in cell
bodies in addition to the most intense immunoreactivity in dendritic spines. Even though these findings were
reported in neurons and not in cardiocytes, the consistency of enzyme distribution on the internal membranes in this immunohistochemical study and in another cytochemical study of similar nerve tissue
(Drescher et al., 1995) supports the likelihood of the
localization of AC within the intracellular organelles of
cardiocytes in animal and human myocardium. A number of biochemical studies have also suggested that
there is AC activity within the sarcoplasmic reticulum
in mammalian myocardium (Katz et al., 1974; Sulakhe
and Dhalla, 1973).
target substrates by cAMP-dependent protein kinase
initiates several different physiological responses. It
has been suggested that this protein kinase is compartmentalized with its substrates so that individual stimulation can preferentially result in phosphorylation of
the specific substrates (Coghlan et al., 1993). For
example, the differential localization of type II cAMPdependent protein kinase is achieved by an interaction
of the regulatory subunit of the enzyme with A-kinase
anchor proteins, which are localized in the sarcoplasmic reticulum of rat cardiocytes (Hausken et al., 1994;
McCartney et al., 1995). Compartmentalization of cAMP
is also suggested by the localization of cyclic GMPinhibited cAMP phosphodiesterase in sarcoplasmic reticulum (Oquist et al., 1992). Beta 1-adrenoceptor agonists and beta 2-adrenoceptor agonists cause differential
compartmentalization of cAMP and cAMP-dependent
protein kinase in cardiac muscle (Yabana et al., 1995).
In addition to the compartmentalization of cAMPdependent protein kinase and cAMP, preferential activation of a specific signal function following individual
stimulation could also be regulated by a compartmentalization of AC to subcellular locations. In a previous
biochemical study which indicated compartmentalization of cAMP and cAMP-dependent protein kinase in
Significance of the Enzyme Distribution
on Internal Membranes of Cardiocytes
The signal transduction mediated by a cascade of AC,
cAMP, and cAMP-dependent protein kinase regulates a
variety of biochemical events. The phosphorylation of
AC DISTRIBUTION IN CARDIOCYTES
485
Fig. 7. Electron micrographs of ventricular myocardial biopsies. The AC reaction products are seen in
association with various subcellular structures (arrows). Some of the structures are vesicles of different
size (a, b) and others are membranous (c) or tubular (d) structures. They are often unclear as to structural
origin.
rabbit cardiocytes (Buxton and Brunton, 1983), it was
proposed that the compartmentalization begins at the
level of hormone-receptor AC complex, whereas the
location of the compartment was speculated to be on
sarcolemma. The distribution of cytochemical enzyme
activity within a variety of intracellular membranes in
the present study may reflect exactly such compartmentalization of AC within cardiocytes. AC activity within
the sarcoplasmic reticulum most likely represents a
regulatory function by signal transduction for calcium
handling by the sarcoplasmic reticulum (calcium uptake, release or binding) (Yamamoto et al., 1991).
Nuclear trafficking of the catalytic subunit of cAMPdependent protein kinase is critical for a regulation of
gene expression and the localization of both catalytic
unit and regulatory subunits of protein kinase has been
demonstrated in cell nuclei of various rat tissues (Trinczek et al., 1993). Active or passive mechanisms have
been suggested for nuclear import and export of this
enzyme protein (Harootunian et al., 1993; Wen et al.,
1995). AC distributed on the nuclear envelope in cardiocytes of the present study could regulate nuclear functions, such as gene expression, through a cascade
mediated by cAMP and cAMP-dependent protein kinase. The localization of AC in association with perinuclear parallel cisternae and interlaced tubular structures could also reflect a signal transduction, which
controls nuclear functions through cAMP-dependent
protein kinase. The perinuclear region is a site of
protein synthesis and AC distributed in this subcellular
location could also serve to regulate specific protein
synthesis in cardiocytes.
AC found within membranous structures at the cell
periphery is most likely related to the enzyme activity
linked to hormone receptors on the sarcolemma. The
coated vesicles or pits in the vicinity of this enzyme
localization may support the relation to the hormone
receptors. This enzyme distribution possibly reflects a
putative phenomenon of recycling of hormone receptors
and AC localized on or near the sarcolemma.
Diversity of ACs, such as different amino acid sequence, mode of enzyme activity regulation, and chromosomal location of coding genes among eight isoforms of
the enzyme (Espinasse et al., 1995) may well represent
other key elements for the regulation of preferential
activation of individual signals among multiple poten-
486
S. YAMAMOTO ET AL.
tial signal transductions. The enzyme activity of type V
and VI ACs in mammalian hearts is inhibited by
submicromolar concentrations of Ca21 and, consequently, serve to regulate cardiocyte contractility. The
specific physiologic significance of the differential cardiac expression of these two AC isoforms in relation to
their similar biochemical properties remains unknown
(Espinasse et al., 1995; Katsushika et al., 1992; Yu et
al., 1995).
Another explanation of the localization of the cytochemical enzyme activity within some organelles may
lie in the synthesis of the enzyme or its transport
directed to the sarcolemma. The cytochemical demonstration of AC may represent not only functional activity of the enzyme on the sarcolemma, but collectively all
its potential activity (such as transport) which could be
caused by exposure to NaF and isoproterenol in the
incubation medium.
It has been shown that AC localized on cell membranes is closely linked to cell surface receptors, which
bind to extracellular signals, including hormones (Gilman, 1987; Pastan, 1972; Schramm and Selinger, 1984;
Sutherland, 1972). In the present study of human
cardiocytes, the cytochemical localization of AC was
demonstrated for several different intracellular membranes and the potential significance as a regulatory
mechanism for a specific signal function is postulated.
An essential question now becomes what could be the
upstream signals to regulate AC activity within these
intracellular organelles.
CONCLUSIONS
Intracellular distribution of AC within human cardiocytes was demonstrated with electron microscopic cytochemistry. The enzyme localization in association with
various internal membranes may reflect compartmentalization of AC to sarcoplasmic reticulum, nuclear
envelope, sarcolemma, and other membrane structures
to regulate a preferential signal processing for Ca21
handling, gene expression, and hormone actions within
these cardiocytes.
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