FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating (Pi-regulating) hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth, and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone-specific deletion of Fgf23 on bone and mineral metabolism in the dentin matrix protein 1-knockout (Dmp1KO) mouse model of ARHR. At 12 weeks, Dmp1KO mice showed increased serum FGF23 and parathyroid hormone levels, hypophosphatemia, impaired growth, rickets, and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion, and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impaired osteoprogenitors' differentiation and that DMP1 deficiency contributed to impaired mineralization independent of FGF23 or Pi levels. In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.

Risk of Type 2 Diabetes in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder: A Nationwide Longitudinal Study.

BACKGROUND: Studies have suggested there is an association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes mellitus (DM)-related risk factors, such as obesity, hypertension, and dyslipidemia. However, the association between ADHD and type 2 DM remains unknown. METHODS: Using the Taiwan National Health Insurance Research Database, we enrolled 35,949 adolescents and young adults with ADHD (ICD-9-CM code: 314) and 71,898 (1:2) age- and sex-matched controls from 2002 through 2009 and followed up with them until the end of 2011. Participants who developed type 2 DM during the follow-up period were identified. RESULTS: Adolescents (hazard ratio [HR] = 2.83; 95% CI, 1.96-4.09) and young adults (HR = 3.28; 95% CI, 1.41-7.63) with ADHD had a higher risk of developing type 2 DM than did the controls after adjustment for demographic characteristics, use of ADHD medications and atypical antipsychotics, and medical comorbidities. Individuals with ADHD had a shorter mean ± SD duration between enrollment and onset of type 2 DM (3.17 ± 2.33 vs 4.08 ± 2.11 years, P = .004) during the follow-up compared with the controls. Sensitivity analyses after excluding first-year (HR = 2.36; 95% CI, 1.65-3.38) and first-3-year (HR = 1.92; 95% CI, 1.19-3.09) observation periods were consistent. Long-term use of atypical antipsychotics was associated with a higher likelihood of subsequent type 2 DM (HR = 2.82, 95% CI, 1.74-4.58). DISCUSSION: Adolescents and young adults with ADHD were more likely than non-ADHD controls to develop type 2 DM in later life. In addition, those with ADHD taking atypical antipsychotics exhibited a higher risk. Although correlation does not equal causation, our findings merit further study about the relationship between ADHD and type 2 DM.

Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts. Aims To evaluate the risk of suicide attempt in adolescents and young adults with ADHD. METHOD: Using a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed. RESULTS: ADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19-4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46-9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22-0.97). CONCLUSION: ADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours. Declaration of interest None.

Risk of stroke among patients with borderline personality disorder: A nationwide longitudinal study.

BACKGROUND: Previous studies suggested that patients with borderline personality disorder (BPD) had a higher prevalence of stroke-related risk factors, such as hypertension, dyslipidemia, and diabetes mellitus. But, the association between BPD and subsequent stroke has been rarely investigated. METHODS: Using the Taiwan National Health Insurance Research Database, 5969 borderline patients aged 18 years and older and 23,876 age-and sex-matched controls were enrolled between 2002 and 2009, and followed up to the end of 2011 to identify the development of stroke. RESULTS: The Cox regression model after adjusting for demographic data, psychiatric comorbidities, and medical comorbidities showed that BPD was associated with an increased risk of developing any stroke (HR: 4.82, 95% CI: 2.77-8.40) and ischemic stroke (HR: 5.67, 95% CI: 2.49-12.93). The findings of sensitivity analysis after excluding the first year of observation were consistent: any stroke (HR: 3.44, 95% CI: 1.83-6.47) and ischemic stroke (HR: 4.75, 95% CI: 1.91-11.77). DISCUSSION: Patients with BPD had an elevated vulnerability to subsequent stroke and ischemic stroke compared to those without BPD. Further studies would be required to investigate the underlying mechanisms.

Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study.

BACKGROUNDS: Several cross-sectional studies suggested a link between endometriosis and mood disorders. However, the temporal association between endometriosis and mood disorders (depression and anxiety disorders) is still unclear. METHODS: Using the Taiwan National Health Insurance Research Database, 10,439 women with endometriosis and 10,439 (1:1) age-/sex-matched controls between 1998 and 2009 were enrolled, and followed up to the end of 2011. Those who developed depression or anxiety disorders during the follow-up were identified. RESULTS: Women with endometriosis had an increased risk of developing major depression (hazard ratio [HR]: 1.56, 95% confidence interval [CI]:1.24-1.97), any depressive disorder (HR: 1.44, 95% CI: 1.25-1.65), and anxiety disorders (HR: 1.44, 95% CI: 1.22-1.70) in later life compared to those without endometriosis. Stratified by age group, women with endometriosis aged <40 years and those aged ≧40 years were both prone to developing major depression (HR: 1.52, 95% CI: 1.15-1.99; HR: 1.69, 95% CI: 1.09-2.62), any depressive disorder (HR: 1.43, 95% CI: 1.21-1.69; HR: 1.45, 95% CI: 1.13-1.56), and anxiety disorders (HR: 1.39, 95% CI: 1.14-1.71; HR: 1.53, 95% CI: 1.15-2.04). LIMITATION: the incidence of depression and anxiety disorders may be underestimated since only those who sought medical consultation and help would be enrolled in our study. CONCLUSION: Endometriosis was associated with an elevated likelihood of developing depression and anxiety disorders. Further studies may be required to investigate the underlying pathophysiology between endometriosis and both depression and anxiety disorders.

Bidirectional Association Between Depression and Fibromyalgia Syndrome: A Nationwide Longitudinal Study.

Several cross-sectional studies have reported a common comorbidity between depression and fibromyalgia syndrome (FMS). However, a bidirectional temporal association between these 2 distinct diseases has rarely been investigated. Using the Taiwan National Health Insurance Research Database, 25,969 patients with FMS and without any psychiatric disorder and 17,142 patients with depression and without FMS between 2000 and 2008 were enrolled and separately compared with age- and sex-matched (1:4) control groups. Patients with FMS who developed a new-onset depression and those with depression who developed new-onset FMS were identified during follow-up (to the end of 2011). The conditional Cox regression analyses, after adjustment for demographic data and medical comorbidities, showed that the patients with FMS were associated with an increased risk (hazard ratio [HR] 7.46, 95% confidence interval [CI] 6.77-8.22) of subsequent depression and that those with depression were associated with an increased risk (HR 6.28, 95% CI 5.67-6.96) of subsequent FMS. Our results supported a bidirectional temporal association between depression and FMS. Each disease occurring first may increase the risk of the other subsequently. Further study may be necessary to determine the underlying mechanism between depression and FMS and to clarify whether a prompt intervention for depression or FMS may decrease the risk of the other later in life. Perspective: Our study supported a bidirectional temporal association between depression and FMS such that each disease occurring first may increase the risk of the other subsequently. This result may imply a shared pathophysiology between FMS and depression, but further investigation is needed.

A predisposition for allergies predicts subsequent hypertension, dyslipidemia, and diabetes mellitus among patients with schizophrenia or bipolar disorder: a nationwide longitudinal study.

BACKGROUND: Previous studies have shown that both severe mental disorders (schizophrenia and bipolar disorder) and atopic diseases were associated with an increased risk of metabolic syndrome. However, the role of atopy/the predisposition for allergies in the development of metabolic syndrome is still unknown among those with severe mental disorders. METHODS: Using the Taiwan National Health Insurance Research Database, 5826 patients with schizophrenia or bipolar disorder (1908 with a predisposition for allergies and 3918 without) were enrolled between 1998 and 2008. Those who developed hypertension, dyslipidemia, and/or diabetes mellitus were identified during the follow-up to the end of 2011. RESULTS: A predisposition for allergies increased the risk of developing hypertension (HR: 1.67), dyslipidemia (HR: 1.82), and diabetes mellitus (HR: 1.37) in later life among those with severe mental disorders. A dose-dependent relationship was noted between having more atopic comorbidities and a greater likelihood of hypertension (1 atopic disease: HR: 1.60; ≧ 2 atopic comorbidities: HR: 1.87), dyslipidemia (HR: 1.73; HR: 2.12), and diabetes mellitus (HR: 1.26; HR: 1.69). CONCLUSION: A predisposition for allergies was an independent risk factor for hypertension, dyslipidemia, and diabetes mellitus among patients with schizophrenia or bipolar disorder. Further studies would be required to elucidate the underlying pathophysiology among atopy, schizophrenia, bipolar disorder, and metabolic syndrome.

Higher risk of developing major depression and bipolar disorder in later life among adolescents with asthma: a nationwide prospective study.

OBJECTIVE: Previous studies have suggested an immunological dysfunction in mood disorders, but rarely have investigated the temporal association between allergic diseases and mood disorders. Using the Taiwan National Health Insurance Research Database, we attempted to investigate the association between asthma in early adolescence and the risk of unipolar depression and bipolar disorder in later life. METHODS: In all, 1453 adolescents with asthma aged between 10 and 15 years and 5812 age-/gender-matched controls were selected in 1998-2000. Subjects with unipolar depression and bipolar disorder that occurred up to the end of follow-up (December 31 2010) were identified. RESULTS: Adolescents with asthma had a higher incidence of major depression (2.8% vs. 1.1%, p < 0.001), any depressive disorder (6.1% vs. 2.6%, p < 0.001), and bipolar disorder (1.0% vs. 0.3%, p < 0.001) than the control group. Cox regression analysis showed that asthma in early adolescence was associated with an increased risk of developing major depression (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.14-2.89), any depressive disorder (HR: 1.74, 95% CI: 1.27-2.37), and bipolar disorder (HR: 2.27, 95% CI: 1.01-5.07), after adjusting for demographic data and comorbid allergic diseases. DISCUSSION: Adolescents with asthma had an elevated risk of developing mood disorders in later life. Further studies would be required to investigate the underlying mechanisms for this comorbid association and elucidate whether prompt intervention for asthma would decrease the risk of developing mood disorders.

Higher risk of developing mood disorders among adolescents with comorbidity of attention deficit hyperactivity disorder and disruptive behavior disorder: a nationwide prospective study.

Attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) are frequently comorbid. Previous studies suggested that the comorbidity of CD and ODD in ADHD may increase the risk of a further development of mood disorder, but most studies had a small sample size. Using a population-based prospective study design, a large sample composed of 1277 adolescents with ADHD-alone, 46 with ADHD + ODD, 87 with ADHD + CD, and 5640 age/gender-matched controls were enrolled in 2003. These cases were followed to 2010 to identify the cases developing unipolar depressive disorder and bipolar disorder. ADHD + CD groups exhibited a higher prevalence of unipolar depressive disorder (23.0% vs. 13.0% vs. 8.7% vs. 0.7%, p < 0.001) and bipolar disorder (3.4% vs. 2.2% vs. 1.3% vs. 0.2%, p < 0.001) than ADHD + ODD group, ADHD-alone group, and control group. Adolescents with ADHD + CD, those with ADHD + ODD, and those with ADHD-alone had a higher likelihood of developing unipolar depressive disorder (hazard ratio [HR]: 44.34, 95% confidence interval [CI]: 23.95-71.36; HR: 18.76, 95%CI: 7.87-44.71; HR: 13.01, 95%CI: 8.99-18.82) and bipolar disorder (HR: 14.39, 95%CI: 4.00-51.80; HR: 8.32, 95%CI: 1.06-65.32; HR: 5.24, 95%CI: 2.44-11.24) than the controls. Adolescents with ADHD had elevated risks of unipolar depression and bipolar disorder in their later life, and especially, those with ADHD and comorbidity of CD or ODD exhibited the highest risk. Further study would be required to evaluate whether prompt intervention for ADHD and disruptive behavior problems would decrease the risk of developing mood disorder.

Attention deficit hyperactivity disorder, tic disorder, and allergy: is there a link? A nationwide population-based study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and tic disorder usually co-occur in the same individuals, but the underlying mechanisms remain unclear. Previous evidence has shown that a frequent coexistence of allergic diseases was noted in patients with ADHD or tic disorder. We attempted to investigate the possible link among ADHD, tic disorder, and various allergic diseases. METHODS: Utilizing the Taiwan National Health Insurance Research Database from 1996 to 2010, 5,811 patients with ADHD alone, 1,816 patients with tic disorder alone, and 349 patients with dual diagnoses of ADHD and tic disorder were identified and compared with age-/gender-matched controls (1:4) in an investigation of the association among ADHD, tic disorder, and allergic diseases. RESULTS: Patients with dual diagnoses of ADHD and tic disorder had a significantly higher prevalence of allergic diseases and psychiatric comorbidities, including allergic rhinitis (43% vs. 28.4% vs. 33.6% vs. 19.7%, p < 0.001), asthma (27.5% vs. 17.2% vs. 18.2% vs. 11.9%, p < 0.001), atopic dermatitis (10.6% vs. 8.4% vs. 7.0 vs. 5.9%, p < 0.001), allergic conjunctivitis (55.6% vs. 34.7% vs. 43.5% vs. 26.3%, p < 0.001), obsessive compulsive disorder (4.0% vs. 1.3% vs. 2.0% vs. 0.1%, p < 0.001), and anxiety disorder (22.1% vs. 18.0% vs. 6.0% vs. 0.5%, p < 0.001) than the ADHD alone group, the tic alone group, and the control group. Furthermore, ADHD patients with more allergic diseases (≥ 3 comorbidities: OR: 3.73, 95% CI: 2.65~5.25; 2 comorbidities: OR: 2.52, 95% CI: 1.82~3.47; 1 comorbidity: OR: 1.87, 95% CI: 1.41~2.49) exhibited an increased risk of tic disorder compared with ADHD patients without allergic disease. CONCLUSION: A significant association among ADHD, tic disorder, and allergic diseases was noted in our study. The results may inspire further studies to clarify the underlying mechanisms and help us understand more about the complex etiology of ADHD, tic disorder, and their co-occurrence.

Crude caffeine reduces memory impairment and amyloid ß(1-42) levels in an Alzheimer's mouse model.

Alzheimer's disease (AD), a chronic neurodegenerative disorder associated with the abnormal accumulations of amyloid ß (Aß) peptide and oxidative stress in the brain, is the most common form of dementia among the elderly. Crude caffeine (CC), a major by-product of the decaffeination of coffee, has potent hydrophilic antioxidant activity and may reduce inflammatory processes. Here, we showed that CC and pure caffeine intake had beneficial effects in a mouse model of AD. Administration of CC or pure caffeine for 2months partially prevented memory impairment in AD mice, with CC having greater effects than pure caffeine. Furthermore, consumption of CC, but not pure caffeine, reduced the Aß(1-42) levels and the number of amyloid plaques in the hippocampus. Moreover, CC and caffeine protected primary neurons from Aß-induced cell death and suppressed Aß-induced caspase-3 activity. Our data indicate that CC may contain prophylactic agents against the cell death and the memory impairment in AD.

The calcium-sensing receptor-dependent regulation of cell-cell adhesion and keratinocyte differentiation requires Rho and filamin A.

Extracellular Ca(2+) (Ca(2+)(o)) functioning through the calcium-sensing receptor (CaR) induces E-cadherin-mediated cell-cell adhesion and cellular signals mediating cell differentiation in epidermal keratinocytes. Previous studies indicate that CaR regulates cell-cell adhesion through Fyn/Src tyrosine kinases. In this study, we investigate whether Rho GTPase is a part of the CaR-mediated signaling cascade regulating cell adhesion and differentiation. Suppressing endogenous Rho A expression by small interfering RNA (siRNA)-mediated gene silencing blocked the Ca(2+)(o)-induced association of Fyn with E-cadherin and suppressed the Ca(2+)(o)-induced tyrosine phosphorylation of ß-, γ-, and p120-catenin and formation of intercellular adherens junctions. Rho A silencing also decreased the Ca(2+)(o)-stimulated expression of terminal differentiation markers. Elevating the Ca(2+)(o) level induced interactions among CaR, Rho A, E-cadherin, and the scaffolding protein filamin A at the cell membrane. Inactivation of CaR expression by adenoviral expression of a CaR antisense complementary DNA inhibited Ca(2+)(o)-induced activation of endogenous Rho. Ca(2+)(o) activation of Rho required a direct interaction between CaR and filamin A. Interference of CaR-filamin interaction inhibited Ca(2+)(o)-induced Rho activation and the formation of cell-cell junctions. These results indicate that Rho is a downstream mediator of CaR in the regulation of Ca(2+)(o)-induced E-cadherin-mediated cell-cell adhesion and keratinocyte differentiation.

Solanum erianthum intoxication mimicking an acute cerebrovascular disease.

We describe a case of Solanum erianthum poisoning that happened to a 75-year-old man. He ate the S erianthum that he gathered from the countryside, believing that it would be helpful in improving the numbness of his distal limbs. S erianthum is a solanaceous plant that contains a variable concentration of solanum alkaloids, causing gastrointestinal irritation, and tropane alkaloids that have anticholinergic properties producing typical and sometimes severe atropinelike symptoms. The diagnosis of S erianthum poisoning was made based on clinical symptoms and signs of anticholinergic syndrome associated with a history of vegetable meal from countryside and, moreover, on identification of the vegetable obtained from his family. Gastrointestinal decontamination and symptomatic treatment were useful in treatment of acute poisoning.

Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes.

Extracellular Ca(2+) (Ca(2+)(o)) is a critical regulator that promotes differentiation in epidermal keratinocytes. The calcium sensing receptor (CaR) is essential for mediating Ca(2+) signaling during Ca(2+)(o)-induced differentiation. Inactivation of the endogenous CaR-encoding gene CASR by adenoviral expression of a CaR antisense cDNA inhibited the Ca(2+)(o)-induced increase in intracellular free calcium (Ca(2+)(i)) and expression of terminal differentiation genes, while promoting apoptosis. Ca(2+)(o) also instigates E-cadherin-mediated cell-cell adhesion, which plays a critical role in orchestrating cellular signals mediating cell survival and differentiation. Raising Ca(2+)(o) concentration ([Ca(2+)](o)) from 0.03 to 2 mm rapidly induced the co-localization of alpha-, beta-, and p120-catenin with E-cadherin in the intercellular adherens junctions (AJs). To assess whether CaR is required for the Ca(2+)(o)-induced activation of E-cadherin signaling, we examined the impact of CaR inactivation on AJ formation. Decreased CaR expression suppressed the Ca(2+)(o)-induced AJ formation, membrane translocation, and the complex formation of E-cadherin, catenins, and the phosphatidylinositol 3-kinase (PI3K), although the expression of these proteins was not affected. The assembly of the E-cadherin-catenin-PI3K complex was sensitive to the pharmacologic inhibition of Src family tyrosine kinases but was not affected by inhibition of Ca(2+)(o)-induced rise in Ca(2+)(i). Inhibition of CaR expression blocked the Ca(2+)(o)-induced tyrosine phosphorylation of beta-, gamma-, and p120-catenin, PI3K, and the tyrosine kinase Fyn and the association of Fyn with E-cadherin and PI3K. Our results indicate that the CaR regulates cell survival and Ca(2+)(o)-induced differentiation in keratinocytes at least in part by activating the E-cadherin/PI3K pathway through a Src family tyrosine kinase-mediated signaling.

Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes.

Store-operated calcium entry depicts the movement of extracellular Ca2+ into cells through plasma membrane Ca2+ channels activated by depletion of intracellular Ca2+ stores. The members of the canonical subfamily of transient receptor potential channels (TRPC) have been implicated as the molecular bases for store-operated channels (SOC). Here we investigate the role of phospholipase C (PLC) in regulation of native SOC and the expression of endogenous TRPC in human epidermal keratinocytes. Calcium entry in response to store depletion with thapsigargin was reversibly blocked by 2-aminoethoxydiphenyl borane, an effective SOC inhibitor, and suppressed by the diacylglycerol analoge, 1-oleoyl-2-acetyl-sn-glycerol. Inhibition of PLC with U73122 or transfection of a PLCgamma1 antisense cDNA construct completely blocked SOC activity, indicating a requirement for PLC, especially PLCgamma1, in the activation of SOC. RT-PCR and immunoblotting analyses showed that TRPC1, TRPC3, TRPC4, TRPC5, and TRPC6 are expressed in keratinocytes. Knockdown of the level of endogenous TRPC1 or TRPC4 inhibited store-operated calcium entry, indicating they are part of the native SOC. Co-immunoprecipitation studies demonstrated that TRPC1, but not TRPC4, interacts with PLCgamma1 and the inositol 1,4,5-trisphosphate receptor (IP3R). The association of TRPC1 with PLCgamma1 and IP3R decreased in keratinocytes with higher intracellular Ca2+, coinciding with a downregulation in SOC activity. Our results indicate that the activation of SOC in keratinocytes depends, at least partly, on the interaction of TRPC with PLCgamma1 and IP3R.

cDNA cloning and functional expression of a Ca2+-sensing receptor with truncated C-terminal tail from the Mozambique tilapia (Oreochromis mossambicus).

The complete cDNA sequence of the tilapia extracellular Ca(2+)-sensing receptor (CaR) was determined. The transcript length of tilapia CaR (tCaR) is 3.4 kbp and encodes a 940-amino acid, 7-transmembrane domain protein that is consistent in its structural features with known mammalian and piscine CaRs. The tCaR extracellular domain includes a characteristic hydrophobic segment, conserved cysteine residues that are implicated in receptor dimerization (Cys(129) and Cys(131)) and in coupling to the transmembrane domain (nine conserved cysteine residues), and conserved serine residues (Ser(147) and Ser(169-171)) that are linked to receptor binding of Ca(2+) and L-amino acid-mediated potentiation of function. mRNA expression of tCaR was strong in kidney, brain, and gill. Weaker expression was observed in pituitary, stomach, intestine, urinary bladder, and heart. This distribution is consistent with possible physiological roles in endocrine cells, excitable tissues, and ion-transporting barrier epithelia. Expression of tCaR mRNA in kidney and intestine was salinity-dependent, suggesting a role for the receptor in iono-/osmoregulation in this euryhaline teleost species. Human embryonic kidney-293 cells transiently transfected with tCaR cDNA demonstrated dose-dependent phospholipase C activation in response to elevations in the extracellular Ca(2+) concentration ([Ca(2+)](o)). Functional activation of the mitogen-activated protein kinase cascade by high [Ca(2+)](o) was also confirmed in these cells despite the naturally occurring truncation of the receptor's intracellular tail, which removes segments variably linked in mammalian CaRs to filamin-coupled activation of mitogen-activated protein kinase cascades. Sensitivity of phospholipase C activation to [Ca(2+)](o) was dependent on the ionic strength of the bathing medium, supporting a role in salinity sensing.