Queer Current and Pacemaker: The Hyperpolarization-Activated Cation Current in Neurons

Pape, Hans‐Christian

doi:10.1146/annurev.ph.58.030196.001503

Cited by 1,042 publications

(731 citation statements)

References 84 publications

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“…Similarly to the SEH (Fig. 4B), Ih reversion is not observable in the conditions of current-clamp recordings, because Ih reversal potential [approximately Ϫ35 mV (26)] is above the Ih activation range, and Ih amplitude increases with hyperpolarization (25). This suggests that SEHs could be mediated by a temporary inhibition of Ih.…”

Section: Chemical Transmission Is Mediated By the Temporary Inhibitiomentioning

confidence: 92%

“…4A). Interestingly, DAergic neurons display a potent depolarizing current activated by hyperpolarization (Ih) below Ϫ45 mV (25), constitutively active at DAergic neuron resting membrane potential and responsible for the typical sag in membrane potential response to hyperpolarizing current pulses observed in these neurons. Similarly to the SEH (Fig.…”

Section: Chemical Transmission Is Mediated By the Temporary Inhibitiomentioning

confidence: 99%

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Chemical transmission between dopaminergic neuron pairs

Vandecasteele

Głowiński

Deniau

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Midbrain dopaminergic (DAergic) neurons play a major regulatory role in in goal-directed behavior and reinforcement learning. DAergic neuron activity, and therefore spatiotemporal properties of dopamine release, precisely encodes reward signals. Neuronal activity is shaped both by external afferences and local interactions (chemical and electrical transmissions). Numerous hints suggest the existence of chemical interactions between DAergic neurons, but direct evidence and characterization are still lacking. Here, we show, using dual patch-clamp recordings in rat brain slices, a widespread bidirectional chemical transmission between DAergic neuron pairs. Hyperpolarizing postsynaptic potentials were partially mediated by D2-like receptors, and entirely resulted from the inhibition of the hyperpolarization-activated depolarizing current (Ih). These results constitute the first evidence in paired recordings of a chemical transmission relying on conductance decrease in mammals. In addition, we show that chemical transmission and electrical synapses frequently coexist within the same neuron pair and dynamically interact to shape DAergic neuron activity.electrical synapses ͉ paired recordings ͉ substantia nigra pars compacta ͉ Ih T he substantia nigra pars compacta (SNc) is the main modulatory nucleus of basal ganglia, a network of subcortical nuclei involved in procedural learning and habit formation (1, 2). Dopaminergic (DAergic) neurons composing SNc mainly project to the dorsal striatum, the major input nucleus of basal ganglia. In striatum, dopamine (DA) potently modulates the processing of corticostriatal information (3-5), contributing to the formation of sensory-motor linkages allowing selection of adapted motor behavior in response to environmental cues.Nigrostriatal DAergic neurons display two modes of discharge: a tonic firing associated with a low but constant DA release supporting a permanent tune-up of the striatal network, and a phasic firing leading to peaks of DA release, coding for a predictive reward value and attention to salient environmental events (6-9). These modes of activity are controlled by intrinsic electrophysiological properties, external inputs, and local interactions (chemical and electrical synapses) between DAergic neurons. SNc DAergic neurons are connected by gap junctions (10), and display electrical coupling able to control their spontaneous tonic activity (11). Yet, electrical coupling might not be their sole mode of communication. Numerous hints strongly support the existence of chemical transmission. DAergic neurons are known to release DA from dendrites (12), bear autoreceptors, and display a characteristic hyperpolarization in response to DA (13,14) or DA agonist application (15, 16), and to electrical stimulation of the SNc (17) or the subthalamus (18). Moreover, ultrastructural studies revealed the presence of dendrodendritic synaptic contacts between DAergic cells in the SNc (19,20). However, a direct demonstration of neuron-to-neuron communication allowing the characteriza...

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Section: Chemical Transmission Is Mediated By the Temporary Inhibitiomentioning

confidence: 92%

Section: Chemical Transmission Is Mediated By the Temporary Inhibitiomentioning

confidence: 99%

Chemical transmission between dopaminergic neuron pairs

Vandecasteele

Głowiński

Deniau

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…cationic currents are responsible for generating spontaneous pacemaker potentials in the heart (1-3) and in the central nervous system (4). Four members of the HCN family, HCN1-4, have been identified and extensively characterized in heterologous cells (5)(6)(7)(8)(9).…”

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confidence: 99%

Proteolytic Processing of HCN2 and Co-assembly with HCN4 in the Generation of Cardiac Pacemaker Channels

Nerbonne

2009

Journal of Biological Chemistry

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In sino-atrial and atrio-ventricular nodal cells, hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current carrying cationic channels, I f , are expressed that contribute importantly to the diastolic depolarization critical for cardiac pacemaker activity. Although previous studies have demonstrated myocardial expression of both the HCN2 and HCN4 subunits, the specific roles of these subunits in the generation of functional myocardial I f channels remain unclear. To explore the molecular compositions of functional cardiac I f channels, antibodies targeted against specific C-and N-terminal sequences in HCN2 and HCN4 were exploited to examine HCN2 and HCN4 subunit expression in adult (mouse) heart and to immunoprecipitate endogenous HCN-encoded cardiac I f channel complexes. Western blot experiments revealed that although the full-length HCN2 (105 kDa) and HCN4 (160 kDa) proteins are readily detected in transiently transfected HEK-293 cells and in adult (mouse) brain, the molecular mass of the HCN2 protein in the myocardium is ϳ60 kDa. In addition, the myocardial 60-kDa HCN2 protein lacks the C terminus, which contains the cAMP binding domain. In heterologous cells, the C-terminal-truncated HCN2 protein co-assembles with HCN4 to form functional heteromeric HCN channels, which activate faster than homomeric HCN2 or homomeric HCN4 channels, and display properties similar to endogenous myocardial I f channels Taken together, these results suggest that functional myocardial I f channels reflect the heteromeric assembly of HCN2 and HCN4 subunits and further that the HCN4 subunit underlies the cAMP-mediated regulation of cardiac I f channels.Hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 cationic currents are responsible for generating spontaneous pacemaker potentials in the heart (1-3) and in the central nervous system (4). Four members of the HCN family, HCN1-4, have been identified and extensively characterized in heterologous cells (5-9). Similar to voltage-gated K ϩ (Kv) channels, each HCN channel subunit contains six transmembrane domains and a pore region with a GYG signature motif (5, 6). Heterologous expression of the various HCN subunits reveals hyperpolarization-activated cationic inward currents with distinct voltage-and time-dependent properties, as well as differential sensitivities to cAMPdependent modulation (8, 9). In the myocardium, HCN4 is the most abundantly expressed transcript (5), whereas HCN1 is the primary HCN transcript in brain (5) and HCN2 is readily detected in both heart and brain (7). Previous studies have shown that the conserved N-terminal 52-amino acid sequence in each of the HCN proteins plays critical roles in channel assembly and trafficking (10). In addition, there is a cyclic nucleotide binding domain (120 amino acids) in the C termini of the HCN subunits (8,11,12), although the C-terminal amino acid sequences of each (HCN1-4) of the HCN proteins are distinct.Although the molecular compositions of functional cardiac and neuronal I f channels have not bee...

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“…The hyperpolarization-activated pacemaker current I f /I h has an established role in underlying generation and neurotransmitter-mediated modulation of cardiac pacemaker activity (1) and control of excitability and other functions, including integration of synaptic activity and modulation of synaptic strength, in several different types of neurons (2,3). The molecular correlates of f/h channels are the hyperpolarizationactivated cyclic nucleotide-gated channels, of which four isoforms (HCN1-4) are known.…”

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confidence: 99%

Interaction of the Pacemaker Channel HCN1 with Filamin A

Gravante

Barbuti

Milanesi

et al. 2004

Journal of Biological Chemistry

109

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Pacemaker channels are encoded by the HCN gene family and are responsible for a variety of cellular functions including control of spontaneous activity in cardiac myocytes and control of excitability in different types of neurons. Some of these functions require specific membrane localization. Although several voltagegated channels are known to interact with intracellular proteins exerting auxiliary functions, no cytoplasmic proteins have been found so far to modulate HCN channels. Through the use of a yeast two-hybrid technique, here we showed that filamin A interacts with HCN1, an HCN isoform widely expressed in the brain, but not with HCN2 or HCN4. Filamin A is a cytoplasmic scaffold protein with actin-binding domains whose main function is to link transmembrane proteins to the actin cytoskeleton. Using several HCN1 C-terminal constructs, we identified a filamin A-interacting region of 22 amino acids located downstream from the cyclic nucleotide-binding domain; this region is not conserved in HCN2, HCN3, or HCN4. We also verified by immunoprecipitation from bovine brain that the filamin A-HCN1 interaction is functional in vivo. In filamin A-expressing cells (filamin ؉ ), HCN1 (but not HCN4) channels were expressed in hot spots, whereas they were evenly distributed on the membrane of cells lacking filamin A (filamin ؊ ) indicating that interaction with filamin A affects membrane localization. Also, in filamin ؊ cells the gating kinetics of HCN1 were strongly accelerated relative to filamin ؉ cells. The interaction with filamin A may contribute to localizing HCN1 channels to specific neuronal areas and to modulating channel activity.

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Queer Current and Pacemaker: The Hyperpolarization-Activated Cation Current in Neurons

Cited by 1,042 publications

References 84 publications

Chemical transmission between dopaminergic neuron pairs

Chemical transmission between dopaminergic neuron pairs

Proteolytic Processing of HCN2 and Co-assembly with HCN4 in the Generation of Cardiac Pacemaker Channels

Interaction of the Pacemaker Channel HCN1 with Filamin A

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