D1 Receptors Physically Interact with N-Type Calcium Channels to Regulate Channel Distribution and Dendritic Calcium Entry

Abstract

Dopamine signaling through D1 receptors in the prefrontal cortex (PFC) plays a critical role in the maintenance of higher cognitive functions, such as working memory. At the cellular level, these functions are predicated to involve alterations in neuronal calcium levels. The dendrites of PFC neurons express D1 receptors and N-type calcium channels, yet little information exists regarding their coupling. Here, we show that D1 receptors potently inhibit N-type channels in dendrites of rat PFC neurons. Using coimmunoprecipitation, we demonstrate the existence of a D1 receptor-N-type channel signaling complex in this region, and we provide evidence for a direct receptor-channel interaction. Finally, we demonstrate the importance of this complex to receptor-channel colocalization in heterologous systems and in PFC neurons. Our data indicate that the N-type calcium channel is an important physiological target of D1 receptors and reveal a mechanism for D1 receptor-mediated regulation of cognitive function in the PFC.

Gain in sensitivity and loss in temporal contrast of STDP by dopaminergic modulation at hippocampal synapses

“…Consistent with this idea, STDP rules can be altered by manipulating the shape and their back propagation of dendritic action potentials (40,41). Also, it is well known that dopamine can modulate calcium channels, potassium channels, and even calcium release from intracellular stores (31,(42)(43)(44). Indeed, it has been observed that dopamine increased the propagation of dendritic action potential in a subpopulation of hippocampal neurons (45).…”

G protein inhibition of CaV2 calcium channels

“…31,32 All of these mechanisms terminate G protein signaling and thus channel modulation, but in some cases, direct GPCR-Ca V 2 interactions have been demonstrated that result in endocytic removal of the channel from the plasma membrane upon GPCR desensitization. [33][34][35] Inhibition of Ca 2+ Channels by G Protein βγ…”

“…183 D1 and D2 dopamine receptors also bind directly to Ca V 2.2 channels and modulate channel trafficking 33,184 and GABA B receptors also lead to channel internalization although the mechanism is somewhat different. 34 It is also worth noting that point mutations linked to familial hemiplegic migraine (FHM mutations) have been identified in Ca V 2.1 and lead to complex alterations in channel function.…”

Compartmentalization of the GABABReceptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

“…One possibility is that presynaptic inhibition arises from reduction in the number of available signaling molecules at the plasma membrane of boutons. For example, agonist-induced cointernalization of Ca V 2.2 channel with GPCRs such as opioid-like-receptor ORL1 and dopamine D1 receptor have been observed in earlier studies (Altier et al, 2006;Altier and Zamponi, 2008;Kisilevsky et al, 2008). To test whether the membrane fraction of GB 1a Rs depends on activity-dependent concentration of GABA in the vicinity of boutons, we measured fluorescence of pHluorin, N-terminally tagged to the GB 1a protein as function of neuronal activity or agonist stimulation.…”