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J T Potts

Publications and source records attributed to J T Potts.

At least 55 records · Page 3Linked to original sources
PubMed1995

Cardiopulmonary baroreceptors modulate carotid baroreflex control of heart rate during dynamic exercise in humans.

Numerous studies have reported that, at rest, maximal carotid baroreflex gain is modulated by cardiopulmonary baroreceptors. The purpose of this study was to measure the maximal gain for carotid baroreflex control of heart rate (HR) and blood pressure [mean arterial pressure (MAP)] during dynamic exercise alone and when exercise was accompanied by two levels of cardiopulmonary baroreceptor unloading. Lower body negative pressure (LBNP) produced similar reductions in central venous pressure (CVP) at rest and during exercise. Baroreflex gain for HR at rest was not affected by low-level LBNP but was significantly increased by high-level LBNP [-0.31 +/- 0.05 to -0.57 +/- 0.23 beats.min-1.mmHg-1 carotid sinus pressure (CSP), no LBNP vs. high-level LBNP, P < 0.05]. Exercise combined with low- and high-level LBNP resulted in reflex HR gains (-0.83 +/- 0.44 and -0.83 +/- 0.17 beats.min-1.mmHg-1 CSP, low- vs. high-level LBNP, P < 0.05) that were significantly greater than the algebraic sum of the HR gain measured during exercise and LBNP alone. Neither exercise nor the two levels of LBNP significantly altered baroreflex gain for MAP. The slope relating HR gain to CVP at rest was significant (0.07 +/- 0.02 beats.min-1.mmHg CSP-1.mmHg CVP-1, P < 0.01) and increased 114% during exercise (P < 0.05). A similar analysis of MAP gain found no difference in slope between rest and exercise (P > 0.05). Together these data indicate 1) a tonic inhibitory interaction between cardiopulmonary baroreceptors and carotid baroreflex control of HR during exercise, and 2) a nonlinear relationship between deactivation of cardiopulmonary baroreceptors and changes in carotid baroreflex gain. This interaction may improve overall cardiovascular regulation when central blood volume and/or CVP is reduced, as has been reported during prolonged exercise in the heat.

Adult↗
PubMed1995

Aortic-cardiac reflex during dynamic exercise.

We investigated the aortic-cardiac reflex during low-intensity cycling in 10 healthy volunteers. Baroreflex function was assessed by the ratio of change in heart rate to mean arterial pressure (delta HR/delta MAP) during phenylephrine (PE) infusion. The ratio obtained during PE combined with low-level lower body negative pressure (LBNP) and calculated neck pressure (NP) was assessed as the gain of the aortic-cardiac reflex. Exercise (approximately 25% maximal O2 uptake or 25 +/- 2 W) significantly increased HR from 64 +/- 2 to 98 +/- 2 beats/min, MAP from 90 +/- 3 to 98 +/- 3 mmHg, cardiac output from 6.6 +/- 0.5 to 12.0 +/- 1.4 l/min, and O2 uptake from 3.8 +/- 0.2 to 10.4 +/- 0.6 ml.min-1.kg-1. However, delta MAP (+11.8 +/- 0.4 vs. + 11.3 +/- 0.8 mmHg), delta HR (-12.7 +/- 2 vs. -12.9 +/- 2 beats/min), and delta HR/delta MAP (1.10 +/- 0.19 vs. 1.15 +/- 0.15 beats.min-1.mmHg-1) were not statistically different between rest and exercise during PE. Although PE significantly increased central venous pressure in both supine rest (from 6.7 +/- 0.7 to 10.4 +/- 0.7 mmHg) and exercise (5.8 +/- 0.8 to 8.6 +/- 0.9 mmHg) conditions, when LBNP (-15 +/- 2 vs. -16 +/- 1 Torr for rest vs. exercise) was applied, both rest and exercise central venous pressures were returned to the preinfusion baseline values, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Homolog-scanning mutagenesis of the parathyroid hormone (PTH) receptor reveals PTH-(1-34) binding determinants in the third extracellular loop.

To identify determinants in the rat PTH receptor critical for binding the agonist peptide, PTH-(1-34), we systematically replaced 12 segments (5-33 residues) of the receptor's extracellular surface with the corresponding segments of the homologous rat secretin receptor and screened the resulting mutants in COS-7 cells for altered PTH-(1-34) binding properties. Surface expression of mutant receptors was assessed by the binding of monoclonal antibody 12CA5 to the epitope (HA)-tagged receptors. Of the nine well expressed and therefore informative receptor mutants, four bound radiolabeled PTH-(1-34) at levels that were proportional to the corresponding levels of surface expression, whereas five mutants bound [125I]PTH-(1-34) to levels that were lower than predicted from the cell surface expression levels. These five mutations occurred at the extracellular (EC) end of transmembrane domain 1, the carboxy-terminal portion of the first EC loop, the second EC loop, and the third EC loop. We selected for further fine structure analysis the third EC loop; two specific residues, Trp-437 and Gln-440, were identified at which mutations caused 9- to 16-fold reductions in PTH-(1-34)-binding affinity. The same mutations had little or no effect on the binding affinity of PTH-(3-34). This study provides new information on the location of PTH receptor regions important for high affinity agonist binding and identifies two residues in the third extracellular loop which may contribute to interactions involving the hormone's critical amino terminus.

Amino Acid Sequence↗
PubMed1994

The rat, mouse and human genes encoding the receptor for parathyroid hormone and parathyroid hormone-related peptide are highly homologous.

The organization of the PTH/PTHrP receptor gene is highly homologous in three mammalian species, rat, human and mouse. This gene extends over 22 kb and contains at least 15 exons and 14 introns. The most 5' exon we have identified (exon U) is followed by an approximately 1kb intron. The second exon (exon S) encodes the initiator methionine and the putative signal peptide and is followed by the largest intron of this gene (about 11 kb). The amino-terminal extracellular region is encoded by 4 exons (E1, E2, E3 and G); exon G contains all 4 potential glycosylation sites. Membrane-spanning domains 1-4 and portions of their connecting intracellular and extracellular loops are encoded by 4 exons (M1, M2, M3 and M4). The second extracellular loop and portions of 4th and 5th membrane-spanning domains are encoded by one exon, EL2. The 5th membrane-spanning domain and portion of the 3rd intracellular loop are encoded by one exon, M5. The 6th membrane-spanning domain, the 3rd extracellular loop and the proximal part of the 7th membrane-spanning domain are encoded by one single exon (M6/7); the remaining sequence of the 7th membrane-spanning domain is encoded by a short exon, M7. The carboxy-terminal tail of the receptor and the 3' untranslated region are encoded by one single exon, exon T. The 3' untranslated region does not contain the classical polyadenylation signal, AATAAA. Expression in COS-7 cells of a minigene constructed of a 5' rat cDNA fragment (1.3 Kb) ligated in-frame to a 3' genomic fragment at the NsiI site, which is located in exon M6/7 resulted in a transcript that was translated into a functional receptor; it bound PTH and showed PTH-stimulated accumulation of intracellular cAMP. Therefore, the PTH/PTHrP receptor gene contains alternative 3' sequences that allow cleavage and polyadenylation of its transcript.

Animals↗
PubMed1994

The extracellular amino-terminal region of the parathyroid hormone (PTH)/PTH-related peptide receptor determines the binding affinity for carboxyl-terminal fragments of PTH-(1-34).

The recombinant human PTH/PTH-related peptide (PTHrP) receptor, when transiently expressed in COS-7 cells, binds [Nle8,18,Tyr34] bovine PTH-(7-34)amide [PTH-(7-34)], human PTH-(10-34)amide [PTH-(10-34)], and bovine PTH-(15-34)amide [PTH-(15-34)] with at least 50-fold higher affinity than does the rat receptor homolog. In contrast, PTH-(1-34) binding affinities are similar for both receptor homologs. To map those areas of the PTH/PTHrP receptors that determine the binding specificity for carboxyl-terminal fragments of PTH-(1-34), we constructed chimeric rat/human PTH/PTHrP receptors. These bound PTH-(1-34) with normal affinity and, therefore, must have an overall conformation that resembles that of native receptors. Chimeras with the amino-terminal extracellular domain of the human PTH/PTHrP receptor have a considerably higher binding affinity for PTH-(7-34), PTH-(10-34), and PTH-(15-34) than do the reciprocal receptor constructs in which the amino-terminal region is from the rat PTH/PTHrP receptor. The opossum PTH/PTHrP receptor homolog also binds PTH-(7-34) with higher affinity than the rat receptor, and studies of rat/opossum chimeras confirm the importance of the amino-terminal extracellular domain in determining the PTH-(7-34) binding specificity. Mutant rat and human PTH/PTHrP receptors in which either residues 61-105 of the extracellular region or most of the intracellular tail were deleted have PTH-(7-34) binding characteristics indistinguishable from those of either wild-type receptor. These findings indicate that the amino-terminal extracellular region of the PTH/PTHrP receptor contains a domain(s) that largely determines the binding affinity of amino-terminally truncated PTH analogs. This region, therefore, is likely to constitute a site for ligand-receptor interaction.

Animals↗
PubMed1994

Determinants of [Arg2]PTH-(1-34) binding and signaling in the transmembrane region of the parathyroid hormone receptor.

Previously, we reported that [Arg2]PTH-(1-34) bound to the rat osteosarcoma cell line, ROS 17/2.8, with 2-fold higher apparent affinity than it did to the opossum kidney cell line, OK, yet the analog was only a weak partial agonist for cAMP stimulation with ROS 17/2.8 cells, whereas it was a full cAMP agonist with OK cells. These results suggested that the rat and opossum PTH receptors differ in a region recognized by the hormone's amino-terminus. In this report we show that the cloned PTH receptors derived from ROS 17/2.8 and OK cells, expressed in COS-7 cells, also displayed altered responses to [Arg2]PTH-(1-34). Thus, [Arg2]PTH-(1-34) bound to the cloned rat PTH receptor with 7-fold higher affinity than it did to the cloned opossum PTH receptor, and in cAMP stimulation assays, it was a much weaker agonist with the rat receptor than it was with the opossum receptor. Studies with rat/opossum PTH receptor chimeras suggested that the membrane-spanning region of the receptor contributed to the different binding and signaling responses to [Arg2]PTH-(1-34). Point mutation analysis identified three sites in or near the extracellular ends of transmembrane domains V and VI, which specifically affected [Arg2]PTH-(1-34) binding and signaling.

Amino Acid Sequence↗
PubMed1994

Role of the extracellular regions of the parathyroid hormone (PTH)/PTH-related peptide receptor in hormone binding.

The PTH/PTH-related peptide receptor is a member of a newly discovered family of G-protein-coupled receptors. Strikingly conserved features among these receptors include the positioning of eight extracellular cysteines and several other residues that are located predominantly within the membrane-embedded region. Deletion mutants or receptors with point mutations of the highly conserved cysteine residues were transiently expressed in COS-7 cells to evaluate PTH binding and PTH-stimulated cAMP production. Deletion of residues 61-105, which are encoded by exon E2 in the PTH/PTH-related peptide receptor gene, did not affect receptor function. An epitope derived from Haemophilus influenza hemagglutinin was, therefore, introduced into this portion of most receptors to allow the independent assessment of cell surface expression. PTH binding capacity was not reduced by the deletion of residues 258-278 in the first extracellular loop. Receptors with deletion of either residues 31-47 in the amino-terminal extension or residues 431-440 in the third extracellular loop failed to bind PTH, although expression of the receptor on the cell surface was only marginally reduced. Most other receptor mutants, including those in which each of the six cysteines in the amino-terminus was replaced by serines, failed to be processed and/or expressed appropriately, whereas the substitution of cysteine-281 or -351 had a less severe effect. The combined replacement of both cysteines concomitantly increased PTH binding and cell surface expression, suggesting the formation of a disulfide bond between these two residues. Our data indicate that residues near the amino-terminus and within the third extracellular loop are necessary for ligand binding, whereas more than 25% of the receptor's extracellular region appears not to be involved.

Amino Acid Sequence↗
PubMed1994

Blood pressure responses to dynamic exercise with lower-body positive pressure.

Cardiovascular responses were obtained during cycling with graded levels of lower-body positive pressure (LBPP) applied to the exercising limbs. Seven men performed four incremental work rate (25 W.min-1) exercise (IWREx) tests to their limit of tolerance while exposed to 0, 15, 30, or 45 Torr LBPP. They also performed four, 6-min constant work rate exercise (CWREx) bouts at two work rates with LBPP's of 0 and 45 Torr. Cardiovascular data were obtained at rest and at 40%, 55%, 75%, and 90% of VO2peak, as well as at minute 5 of CWREx. LBPP did not alter VO2, HR, SV, or cardiac output (Qc) responses at rest or during exercise. However, both 30 and 45 Torr LBPP produced increases in MAP at rest and during exercise (P < 0.05). During CWREx, elevations in blood pressure were mediated via increases in TPR (P < 0.05). Only 45 Torr LBPP elicited a significantly greater blood pressure increase during exercise than rest, suggesting muscle blood flow restriction at this level of LBPP was sufficient to activate a muscle metabo-reflex. These findings suggest that the muscle metabo-reflex is not tonically active during dynamic exercise under normal conditions, but may instead require a critical reduction in muscle blood flow before it is activated.

Adult↗
PubMed1993

Carotid baroreflex responsiveness to lower body positive pressure-induced increases in central venous pressure.

Lower body positive pressure (LBPP) was applied at 4 and 30 Torr to increase central venous pressure (CVP). CVP increased with LBPP (r = 0.55, P < 0.01), and the increases were significant at 4 and 30 Torr (7.4 and 7.8 mmHg) from the control (6.0 mmHg). During LBPP cardiac output increased, which was significantly related to the increase in CVP (r = 0.63, P < 0.01). The carotid baroreflex was elicited by trains of neck pressure and suction from 40 to -65 Torr. The carotid-cardiac and carotid-vasomotor baroreflex responses were assessed by determining the maximal gains of heart rate (HR) interval and intraradial mean arterial pressure (MAP) to changes in carotid sinus pressure using a logistic model. The carotid-cardiac and carotid-vasomotor baroreflex gains were negatively related to LBPP, and at 30 Torr, both gains (5.6 ms/mmHg and -0.14 mmHg/mmHg) were significantly smaller than the control (12.4 ms/mmHg and -0.24 mmHg/mmHg). The decreases in carotid-cardiac and carotid-vasomotor baroreflex sensitivity during LBPP were primarily associated with the increases in CVP (r = -0.52, P < 0.01, and r = -0.74, P < 0.01, respectively). These data suggest that the increases in CVP and/or central blood volume diminish the sensitivity of the carotid baroreflex control of HR and MAP by enhancing the tonic inhibitory influence from the cardiopulmonary baroreceptors.

Adult↗
PubMed1993

Carotid baroreflex responsiveness during dynamic exercise in humans.

We utilized 5-s changes of neck pressure and neck suction (from 40 to -80 Torr) to alter carotid sinus transmural pressure in seven men with peak oxygen uptake (VO2peak) of 41.4 +/- 3.6 ml O2.kg-1.min-1. Peak responses of heart rate (HR) and mean arterial pressure (MAP) to each carotid sinus perturbation were used to construct open-loop baroreflex curves at rest and during exercise at 25.7 +/- 1.1 and 47.4 +/- 1.9% VO2peak. The baroreflex curves were fit to a logistic function describing the sigmoidal nature of the carotid sinus baroreceptor reflex. Maximal gain for baroreflex control of HR (-0.31 +/- 0.05 beats.min-1.mmHg-1) and MAP (-0.30 +/- 0.08 mmHg/mmHg) at rest was the same as during exercise at 25 and 50% VO2peak (-0.30 +/- 0.05, -0.39 +/- 0.13 beats.min-1.mmHg-1 for HR, P = NS; -0.23 +/- 0.04, -0.60 +/- 0.38 mmHg/mmHg for MAP, P = NS). Resetting of the baroreflex occurred during exercise at 50% VO2peak. The centering point, threshold, and saturation pressures were significantly increased for baroreflex control of HR (delta pressure = 26.3 +/- 6.8, 19.6 +/- 10.4, 33.0 +/- 5.6 mmHg, P < 0.05) and MAP (delta pressure = 27.1 +/- 7.7, 16.1 +/- 14.8, 38.2 +/- 8.5 mmHg, P < 0.05). The operating point (steady-state HR and MAP) was shifted closer to threshold of the baroreflex during exercise at 50% VO2peak, as reflected by differences in HR and MAP between the centering and operating points (delta HR = 12.5 +/- 4.7 beats/min, P = 0.10; delta MAP = 7.6 +/- 1.3 mmHg, P < 0.05). These findings suggest a resetting of the carotid baroreflex during exercise with no attenuation in maximal sensitivity. A shift in operating point toward threshold of the baroreflex enables effective buffering of elevations in systemic blood pressure via reflex alterations in HR and MAP.

Adolescent↗
PubMed1993

Aortic baroreflex control of heart rate during hypertensive stimuli: effect of fitness.

We examined the aortic baroreflex control of heart rate (HR) in seven healthy young men of average fitness (AF) and seven of high fitness (HF). The fitness level was determined by maximal oxygen uptake (AF = 42.9 +/- 1.1, HF = 62.3 +/- 1.8 ml.kg-1.min-1). Aortic baroreflex control of HR was determined during a steady-state increase of mean arterial pressure (MAP; AF, +15.0 +/- 2.1 and HF, +18.3 +/- 0.8 mmHg) with phenylephrine (PE) infusion combined with positive neck pressure (NP; AF, 18 +/- 2.0 and HF, 20 +/- 0.8 mmHg) to counteract the increased carotid sinus pressure and with low levels of lower body negative pressure to counteract the increased central venous pressure. There was no group difference in the increased MAP or NP, nor was there stage difference in MAP within either group during PE infusion. However, the isolated cardiac-aortic baroreflex gains (i.e., delta HR/delta MAP) were significantly less in the HF (0.16 +/- 0.02 and 0.14 +/- 0.03 beats.min-1.mmHg-1) than in the AF (0.52 +/- 0.08 and 0.59 +/- 0.07 beats.min-1.mmHg-1) subjects at PE + NP and PE + NP + lower body negative pressure. We concluded that during steady-state increases in MAP, the sensitivity of aortic baroreflex control of HR was significantly less in the HF than in the AF subjects.

Adolescent↗
PubMed1993

Analysis of parathyroid hormone's principal receptor-binding region by site-directed mutagenesis and analog design.

Previous deletion studies established that the 25-34 region of PTH is important for receptor binding. We used oligonucleotide-directed mutagenesis to generate 47 different mutations in this region of human (h) PTH-(1-84) and evaluated cAMP-stimulating activity in ROS 17/2.8 cells. The hydrophobic residues Leu24 and Leu28 stood out as mutationally intolerant sites, while neighboring polar residues were comparatively tolerant. A series of synthetic PTH analogs was designed to test these residues further. The affinity of [Tyr34]hPTH-(1-34)NH2 for ROS 17/2.8 cells [dissociation constant (Kd), approximately 5 nM)] was dramatically reduced by the substitution of either Leu24 or Leu28 with Glu (Kd, approximately 20,000 and 8,000 nM, respectively). The Val31-->Glu substitution also sharply reduced affinity (Kd, approximately 200 nM). In contrast, the nearby charge-reversing change of Asp30-->Lys had no effect on binding affinity (Kd, approximately 5 nM). Similar effects were observed in the opposum kidney cell line. The binding of [Tyr34]hPTH-(15-34)NH2 to ROS 17/2.8 and opposum kidney cells (Kd, approximately 10 microM) was abolished by Glu substitutions at position 24, 28, or 31; the Lys30 change was without effect. These results suggest that the adverse effects of the Glu substitutions on receptor binding are not due purely to the disruption of tertiary interactions with the 1-14 region. Circular dichroism spectroscopy indicated that the substitutions do not affect local helical structure. The data suggest that Leu24, Leu28, and Val31 contribute important receptor-binding interactions and are consistent with the hypothesis that an amphipathic alpha-helix in the carboxy-terminal region of PTH-(1-34) is involved in receptor binding.

Amino Acid Sequence↗
PubMed1993

Cloned, stably expressed parathyroid hormone (PTH)/PTH-related peptide receptors activate multiple messenger signals and biological responses in LLC-PK1 kidney cells.

PTH elicits multiple second messenger signals in target cells. This signaling diversity may reflect coupling of a single species of PTH receptors to multiple effectors, the action of different subtypes of PTH receptors, or both. We recently reported the expression cloning, from rat and opossum cells, of closely related cDNAs encoding receptors for PTH [and PTH-related peptide (PTHRP)]. To determine if these cloned PTH/PTHRP receptors can activate multiple intracellular effectors when present at near-physiological levels in intact target cells, we have stably expressed the rat and opossum PTH/PTHRP receptor cDNAs in LLC-PK1 porcine renal epithelial cells. These cells lack endogenous PTH/PTHRP receptors, but do express abundant calcitonin receptors and many features of a proximal tubular phenotype. Subclones of transfected LLC-PK1 cells exhibited high affinity binding (Kd, 1-5 nM) of [Nle8.18,Tyr34]bovine PTH-(1-34)amide (PTH) and dose-dependent activation by PTH of both cAMP accumulation (EC50, 1 nM) and increased release of cytosolic free calcium from intracellular stores (EC50, > or = 20-50 nM) across a wide range of receptor expression. Expressed rat and opossum receptors exhibited similar properties, except for a 5-fold lower binding affinity of the rat receptor for PTH-(7-34). Stimulation by PTH of both cAMP accumulation and elevated cytosolic free calcium was augmented in cells expressing higher numbers of PTH/PTHRP receptors. Like calcitonin, PTH (1-100 nM) reduced the rate of cell proliferation and augmented the rate of inorganic phosphate transport after 24 and 5 h of preincubation, respectively. The growth effect was mimicked by cAMP analogs, forskolin, phorbol esters, and calcium ionophores. Regulation of phosphate transport, however, was mimicked by phorbols, but not by cAMP analogs or forskolin. We conclude that LLC-PK1 cells provide a useful model in which to study the function of cloned PTH/PTHRP receptors. In these cells, a single species of cloned PTH/PTHRP receptors, stably expressed at near-physiological numbers, activates multiple second messenger responses and regulates subsequent biological responses, including at least one (phosphate transport) that is mediated by mechanisms independent of cAMP.

Animals↗
PubMed1993

Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH-related peptide receptor.

Identical complementary DNAs (cDNAs) that encode a 593-amino acid human PTH (PTH)/PTH-related peptide (PTHrP) receptor were isolated by hybridization techniques from two cDNA libraries which had been constructed from human kidney and human osteoblast-like osteosarcoma cells (SaOS-2). Northern blot analysis of total RNA from human bone- and kidney-derived tissue revealed one single major messenger RNA species of about 2.5 kilobases in both tissues. The human PTH/PTHrP receptor has 91% and 81% identity, respectively, with the previously cloned rat and opossum receptors, indicating a high degree of conservation among mammals. Despite this striking degree of amino-acid conservation, the human PTH/PTHrP receptor has several unique biological properties when transiently expressed in COS-7 cells. The apparent dissociation constants for [Nle8,18,Tyr34] bovine PTH(1-34) amide [bPTH(1-34)] are similar for the human and the rat receptor (approximately 8 vs. approximately 15 nM) whereas [Tyr36]PTHrP(1-36) amide has a slightly lower affinity for the human (15-40 nM) than for the rat receptor (approximately 15 nM). Both ligands stimulate efficiently and with similar efficacy the accumulation of intracellular cAMP. The affinities for the antagonists [Nle8,18,Tyr34] bPTH(3.34) amide [bPTH(3-34)] and in particular for [Nle8,18,Tyr34] bPTH(7-34) amide [bPTH(7-34)] are considerably higher for the human receptor, e.g. approximately 8 nM vs. 30 nM for bPTH(3-34) and approximately 100 nM vs. 5000 nM for bPTH(7-34), respectively. Similar biological findings were previously attributed to differences in species- and/or organ-specific PTH/PTHrP receptors. The expression of the recombinant, highly homologous rat and human receptors in a uniform environment indicate that the moderate differences in the primary receptor structure have profound consequences for the receptor binding affinity of amino-terminally truncated PTH analogs. Furthermore, the molecular cloning of identical cDNAs encoding a human PTH/PTHrP receptor from the two major target organs for PTH, bone and kidney, provides strong evidence for one single PTH/PTHrP receptor in both organs, although additional and/or alternatively spliced receptors cannot be excluded.

Amino Acid Sequence↗
PubMed1993

Parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acids are widely distributed in rat tissues.

PTH/PTH-related peptide (PTHrP) receptor mRNAs are widely distributed in rat tissues. PTH and PTHrP, a peptide responsible for hypercalcemia associated with cancers, bind equivalently to common receptors that initially were cloned from rat bone and opossum renal cell cDNA libraries. In this study we used rat PTH/PTHrP receptor cDNA to probe for receptor expression in different rat tissues by Northern blot analysis. PTH/PTHrP receptor transcripts are highly expressed in PTH target tissues, kidney and bone. Receptor transcripts, however, also are expressed in many other tissues, including aorta, adrenal gland, bladder, brain, cerebellum, breast, heart, ileum, liver, lung, skeletal muscle, ovary, placenta, skin, spleen, stomach, uterus, and testes. The major transcript in most tissues is 2.3-2.5 kilobases in size. At least two larger mRNAs are observed in kidney and liver, and smaller transcripts are found in kidney, skin, and testes. The most abundant testicular transcript is 1.4-1.5 kilobases in size, and it hybridizes with two different cDNA probes that encode portions of the receptor sequence from the putative fourth transmembrane domain to its C-terminal end. It does not hybridize, however, with a probe encoding the first 107 residues of the receptor sequence. Although, PTH/PTHrP receptor mRNAs are highly expressed in kidney and bone, classic PTH targets that are associated with calcium homeostasis, their wide tissue distribution suggests that PTH and/or PTHrP have other physiological roles, particularly in these other tissues. The mechanisms leading to tissue-specific expression of PTH/PTHrP receptor transcripts of different sizes and the functions of these mRNAs remain to be determined.

Animals↗