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Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is

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Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients Ghanshyam N. Pandey, Ph.D., Yogesh Dwivedi, Ph.D., Jagadeesh SridharaRao, Ph.D., Xinguo Ren, M.D., Philip G. Janicak, M.D., and Rajiv Sharma, M.D. Phospholipase C (PLC) and protein kinase C (PKC) are significant decrease in PI-PLC and PKC activity and the ␣ ␤ ␤ ␦ important components of the phosphoinositide (PI) expression of selective PKC , I, II, and PLC 1 isozymes signaling system. To examine if the abnormalities observed in membrane and cytosol fraction of platelets from bipolar in the PI signaling system of patients with affective but not unipolar patients. On the other hand, the level of disorders, reported in previous studies, are related to MARCKS was significantly increased in membrane and abnormalities in one or more of its components, we studied cytosol fraction of platelets from patients with bipolar but PKC, PI-PLC activity, the expression of their specific not unipolar disorders. These results suggest that isozymes, and expression of myristoylated alanine-rich alterations in PKC, PLC, and MARCKS may be involved in C-kinase substrate (MARCKS) in platelets obtained from 15 the pathophysiology of bipolar illness. drug-free hospitalized patients with bipolar disorder and 15 [Neuropsychopharmacology 26:216–228, 2002] with major depressive disorder (unipolar) and from 15 © 2002 American College of Neuropsychopharmacology. nonhospitalized normal control subjects. We observed a Published by Elsevier Science Inc. KEY WORDS: Bipolar illness; Unipolar illness; PKC; PLC; drolysis of the substrate, phosphatidyl inositol 4,5-bis- MARCKS; Platelet phosphate (PIP2), by the enzyme phospholipase C (PLC), resulting in the formation of two second messen- In the phosphoinositide (PI) signaling system, agonist gers, inositol 1,4,5-trisphophate (IP ) and diacylglycerol stimulation of G-protein–coupled receptors causes hy- 3 (DAG) (Berridge and Irvine 1989). IP3 stimulates the re- lease of intracellular calcium from the endoplasmic reticulum, and DAG stimulates the enzyme protein ki- From the Psychiatric Institute, Department of Psychiatry College of Medicine, University of Illinois at Chicago, 1601 W. Taylor Street, nase C (PKC) (Nishizuka 1992), which is one of the ma- Chicago, IL 60612 jor intracellular mediators of signals generated by the Address correspondence to: Ghanshyam N. Pandey, Ph.D., Psy- stimulation of cell surface receptors. chiatric Institute, University of Illinois at Chicago, 1601 W. Taylor Street, Chicago, IL 60612. Tel.: (312) 413-4540; E-mail: Several studies indicate abnormalities of the PI sig- [email protected] naling system in patients with unipolar or bipolar dis- Received March 13, 2001; revised June 27, 2001; accepted July 5, orders. It has been reported that the hydrolysis of PIP 2001. 2 Online publication: 7/9/01 at www.acnp.org/citations/Npp by several agonists, such as sodium fluoride (NaF) and 070901146. GTP␥S, is altered in the postmortem brain of depressed NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 2 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00327-X NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 2 PKC, PLC, and MARCKS in Affective Disorders 217 suicide victims and bipolar patients (Jope et al. 1996; acidic and heat-stable protein (Aderem 1992; Black- Pacheco et al. 1996). PI signal transduction determined shear 1993; Aderem 1995) that is highly expressed in by serotonin (5HT)-, thrombin-, and NaF-stimulated IP developing and adult brain. MARCKS contains a basic formation has also been reported to be increased in middle region, termed the effector domain, that binds platelets of depressed patients (Mikuni et al. 1991; Kar- acidic phospholipids, actin, and calcium/calmodulin ege et al. 1996). These abnormalities may be related to (Yamauchi et al. 1998). It also contains PKC phosphory- abnormalities in receptors, such as 5HT2A, 5HT2C, mus- lating sites, which are in close proximity to the effector ␣ carinic M1 and M2, or 2 adrenergic receptors linked to domain. MARCKS is anchored to membranes by an the PI signaling system or to abnormal levels of sub- amino-terminal myristic acid moiety and by the electro- strates, such as PIP2, or to components of the signaling static interaction of the effctor domain to the acidic cascade, such as G-proteins, PKC, or PLC. Abnormali- membrane phospholipids, phosphatidyl serine and ␣ ties in 5HT2A (Pandey et al. 1995), 2 adrenergic recep- PIP2 (McLaughlin and Aderem 1995). MARCKS has tors (Pandey et al. 1990), G-proteins (Garcia-Sevilla et been implicated in many cellular functions, including al. 1997; Karege et al. 1998; Gurguis et al. 1999), and lev- secretion (Goodall et al. 1997), phagocytosis, and actin els of PIP2, a substrate for PI-PLC (Brown et al. 1993; membrane interactions (Allen and Aderem 1995; Myat Soares and Mallinger 1996; Soares et al. 1999), have et al. 1997). MARCKS can inhibit PLC in vitro by se- been reported in platelets of unipolar and/or bipolar questering its substrate, PIP2 (Glaser et al. 1996), sug- patients. gesting that MARCKS may modulate the availability of PLC and PKC are two crucial components of the PI this lipid. signaling system. Both PKC and PLC have been shown Because PKC has been implicated as a possible site to be involved in a variety of physiological functions, for the therapeutic action of lithium, interactions of such as synthesis, release, and reuptake of neurotrans- MARCKS with the short-term and long-term effects of mitters, neuronal development, transcription, long- lithium have been studied in immortalized hippo- term potentiation (LTP), and behavioral responses campal cells as well as in rat brain. Administration of (Nishizuka 1992). Although the role of PLC in affective lithium causes the downregulation of MARCKS in rat disorders has not been fully investigated, some studies hippocampus (Lenox et al. 1992), and in immortalized have shown abnormalities of PLC in depression and hippocampal cells (Watson et al. 1994; Watson and Le- suicide (Pacheco et al. 1996; Pandey et al. 1999). On the nox 1996; Wang et al. 2000), suggesting a relationship other hand, very few studies have examined the role of between bipolar disorders and alteration in MARCKS. PKC in bipolar or unipolar disorders, although PKC Although MARCKS has been studied in postmortem has been implicated in the pathophysiology of bipolar brain of suicide victims (McNarmara et al. 1999), there disorders. For example, it has been reported that PKC have been no studies of MARCKS in patients with bipo- activity as well as translocation of PKC from cytosol to lar or unipolar disorders. membrane are increased in platelets of bipolar patients To test the hypothesis that the abnormalities of the PI and that lithium treatment alters the activity of PKC in signaling system observed in brain and platelets of pa- platelets (Friedman et al. 1993; Wang et al. 1999). Fur- tients with affective disorders may be related to abnor- ther evidence for the involvement of PKC in bipolar malities in one or more of its components, and that disorders is derived from observations that lithium ex- these abnormalities may cause downstream changes in erts significant effects on PKC in a number of cell sys- the PI signaling system, we studied PI-PLC and PKC tems, including central nervous system (CNS) (Manji et activity and expression of their specific isozymes and al. 1993, 1995; Manji and Lenox 1999). Therefore, it has expression of MARCKS in platelets of drug-free pa- been suggested by some investigators that PKC may be tients with unipolar or bipolar disorders and normal an important target for the action of mood stabilizers, control subjects. such as lithium and valproate (Lenox and Manji 1998; Ikonomov and Manji 1999; Jope 1999). Although activation of PKC causes a variety of phys- METHODS iological responses, the steps involved between the acti- Patients vation of PKC and subsequent physiological responses are not known. One approach to examine the molecular These studies were conducted in patients with bipolar steps between the activation of PKC and subsequent or unipolar disorders admitted to the Psychiatric Clini- physiological responses is study of the substrates for cal Research Center, as a part of the General Clinical Re- PKC, which may help in understanding the down- search Center (GCRC), University of Illinois at Chicago. stream events. The activation of PKC causes phosphor- This study was approved by the Institutional Review ylation of a number of membrane-associated protein Board of the University of Illinois at Chicago. substrates, such as myristoylated alanine-rich C-kinase The comparison subjects were nonhospitalized nor- substrate (MARCKS), which is a 30-kilodalton (kD) mal control subjects. The control subjects for unipolar 218 G.N. Pandey et al. NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 2 and bipolar groups were not the same, although the containing 0.2% (wt/vol) Triton X-100. The homoge- number of control subjects is the same in both groups (n ϭ nate was kept at 4ЊC for 60 min with occasional stirring 15). All patients gave informed consent for the study and then centrifuged at 100,000 g for 60 min at 4ЊC. The and were kept drug free for a period of up to 2 weeks. resulting supernatant was used as the membrane frac- During the drug-free washout period, blood was ob- tion. The concentration of protein in these fractions was tained for the studies and clinical assessments were determined using the procedure of Lowry et al. (1951). performed. Normal controls were drug free at the time the blood was drawn and abstained from alcohol at Determination of PKC Activity in Membrane and least 2 days before blood drawing. Cytosol Fractions PKC activity in membrane and cytosol fractions was Clinical Assessments measured by the procedure described earlier by us Patients were diagnosed as having bipolar disorder or (Dwivedi and Pandey 1999a).
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