Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca2+ dependent manner
Introduction
Dopamine modifies neuronal function by interacting with two classes of G protein-coupled receptor families, the D1 family (that includes D1 and D5 receptors) typically coupled to Gs proteins and the D2 family (D2, D3, and D4 receptors) typically couple to Gi proteins (Neve et al., 2004). The rat D3 receptor (D3R) messenger translates a 446 amino acid protein that has 52% homology with the rat D2 receptor; 75% of the homology is in the transmembrane-spanning domains. D3Rs are preferentially expressed in the mesolimbic dopaminergic projection areas, including the nucleus accumbens (NAc) (Sokoloff et al., 1990; Bouthenet et al., 1991). In the nucleus accumbens D3Rs behave as typical D2 family receptors, i.e., they are coupled with Gi proteins inhibiting adenylyl cyclase (Schwartz et al., 1998). Recently it has been shown that D3R function in the NAc is markedly regulated by Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα). In this structure CaMKIIα binds to D3Rs in a Ca2+-sensitive manner, phosphorylating the receptor and inhibiting its function (Liu et al., 2009).
D3Rs are also active in striatonigral nerve endings where they modulate GABA release (Cruz-Trujillo et al., 2013). In these structures the D3R signaling pathway is “atypical”. Instead of acting through coupling to Gi proteins; D3Rs enhance D1R-stimulated cAMP production and GABA release (Cruz-Trujillo et al., 2013). Since CaMKIIα is an abundant enzyme in the brain, especially at synaptic sites (Kelly et al., 1984), we examined whether it also modulates D3Rs signaling localized in presynaptic endings where it is mediated by an “atypical” pathway.
CaMKIIα activity depends on the level of cytoplasmic Ca2+ (Lisman et al., 2002). As cytoplasmic Ca2+ increases, the enzyme is removed from its autoinhibitory state and becomes activated by the binding of Ca2+ and calmodulin (CaM). Activated CaMKIIα phosphorylates its substrates as well as an autophosphorylation site within its autoregulatory domain. The autophosphorylation results in a Ca2+/CaM-independent kinase activity even after the initial Ca2+ stimulus subsides (Hudmon and Schulman, 2002; Colbran and Brown, 2004; Griffith, 2004).
In this study we evaluated whether procedures that markedly enhance cytoplasmic Ca2+ modify the effects of activating D3Rs in the striatal projections to the SNr via a CaMKIIα-mediated process. We concentrated, mostly, on the effects of K+-induced depolarization because this procedure triggers Ca2+-dependent transmitter release that is akin to the naturally occurring process (Bernath, 1992). Furthermore, K+ depolarization of neuronal cultures leads to CaMKIIα accumulation near active zones (AZs) (Tao-Cheng et al., 2006).
Regulation of dopaminergic receptors at presynaptic endings by CaMKIIα is very likely of functional relevance since neural activity modifies presynaptic CaMKIIα activity (see Shakiryanova et al., 2011). An account of our results has already been published in preliminary form (Arturo et al., 2010).
Section snippets
Animals
Male Wistar rats (180–200 g) housed together (five per cage) with water and food available ad libitum and kept under a natural light cycle were used throughout. All the procedures were carried out in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee of the CINVESTAV.
Depletion of endogenous dopamine by reserpine
As indicated in the legends in most experiments rats were pretreated with reserpine (10 mg kg−1, i.p.) 18 h before preparation
Increased cytoplasmic Ca2+ inhibits the potentiating effects of D3 receptor activation on D1 mediated cAMP production
Coactivation of D1Rs and D3Rs stimulate cAMP production and GABA release in SNr (Cruz-Trujillo et al., 2013) .The effects of two treatments, ionomycin and K+-depolarization, that increase cytoplasmic Ca2+ in synaptosomes (Nachshen, 1985; Verhage et al., 1988, 1989) on the cAMP response are illustrated in Fig. 1A and B. D1R stimulation with the selective agonist SKF 38393 (1 μM) increased cAMP production (to 126.3 ± 0.3% in Fig. 1A and to 125.7 ± 1.20% in Fig. 1B, over the control; p < 0.001 for
CaMKIIα modulates D3R receptor function in striatonigral terminals
These experiments establish that CaMKIIα modulates D3R function in the SNr. In this structure D3R activation potentiates the stimulation of GABA release and cAMP accumulation produced by stimulation of D1Rs (Cruz-Trujillo et al., 2013). Two procedures, ionomycin and K+ depolarization, that increase cytoplasmic [Ca2+] blocked D3R mediated stimulation of adenylyl cyclase. The selective CAMKIIα inhibitor KN-62 reversed these blocking effects indicating that CaMKIIα activation mediates this
Acknowledgments
The work was supported by a grant (152326) from CONACyT (México) to BF. We thank Dr. Mimi Halpern for correcting our manuscript.
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