Sex Differences in the Cannabinoid Modulation of an A-Type K⁺ Current in Neurons of the Mammalian Hypothalamus

Abstract

Sex differences in the cannabinoid modulation of an A-type K ϩ current in neurons of the mammalian hypothalamus. J Neurophysiol 94: 2983-2986, 2005. First published May 18, 2005 doi:10.1152/jn.01187.2004. Cannabinoids regulate biological processes governed by the hypothalamus including, but not limited to, energy homeostasis and reproduction. The present study sought to determine whether cannabinoids modulate A-type K ϩ currents (I A ) in neurons of the hypothalamic arcuate nucleus (ARC). Whole cell patch-clamp recordings were performed in slices through the ARC prepared from castrated female and male guinea pigs. Forty percent of guinea pig ARC neurons exhibited a transient outward current that was antagonized by high (mM) concentrations of 4-aminopyridine and (100 nM) rHeteropodatoxin-2. Five of these neurons also were immunopositive for both ␤-endorphin and the Kv4.2 channel subunit. Bath application of the CB1 receptor agonists WIN 55,212-2 (1 M) or ACEA (1 M) selectively induced a rightward shift in the inactivation curve for the I A , significantly increasing the half-maximal voltage without affecting the peak current magnitude, in neurons from female but not male animals. The CB1 receptor antagonist AM251 (1 M) reversed this action. Collectively, these data reveal that guinea pig ARC neurons, including proopiomelanocortin neurons, express a prominent I A that is positively modulated by cannabinoids in a sex-specific way by altering the voltage dependence of its inactivation. The resultant inhibitory effect on this neuronal population may shed some insight into the mechanism(s) by which cannabinoids influence hypothalamic function.

Metabotropic Glutamate Receptor 5 Modulates Nociceptive Plasticity via Extracellular Signal-Regulated Kinase–Kv4.2 Signaling in Spinal Cord Dorsal Horn Neurons

“…These results are consistent with the well known role of A-type potassium channels as important regulators of neuronal excitability (Shibata et al, 2000;Jerng et al, 2004;Varga et al, 2004;Vydyanathan et al, 2005). These findings also fit well with a large body of data implicating a variety of G-protein-coupled receptors as modulators of A-type currents and neuronal excitability (Wang et al, 1997;Starodub and Wood, 2000;Burdakov and Ashcroft, 2002;Tang et al, 2005). In addition, because group I mGluRs have been implicated in various forms of synaptic plasticity (Balschun et al, 1999;Andjus et al, 2005;Grueter et al, 2006;Jung et al, 2006), modulation of A-type currents by group I mGluRs may represent a strategy shared among different types of neurons to adjust their output and might offer a potential mechanism for the effects of group I mGluRs on other types of plasticity such as learning and memory or drug addiction.…”

S3b Amino Acid Substitutions and Ancillary Subunits Alter the Affinity of Heteropoda venatoria Toxin 2 for Kv4.3

“…However, our data do provide a partial explanation for the apparent differences seen in response to HpTx2 between native and heterologously expressed K ϩ currents. We suggest that when applied to native transient K ϩ currents based on Kv4 channels, HpTx2 will be more potent than we have found for Kv4.3 expressed in oocytes in the absence of ancillary subunits (Sanguinetti et al, 1997;Brahmajothi et al, 1999;Guo et al, 1999;Himmel et al, 1999;Ramakers and Storm, 2002;Sanchez et al, 2002;Tang et al, 2005;Lauver et al, 2006;Wang and Schreurs, 2006;Colinas et al, 2008).…”

“…The lines are the fits of the fractional occupancies as described in the text; shown are Kv4. (Sanguinetti et al, 1997;Brahmajothi et al, 1999;Guo et al, 1999Guo et al, , 2005Himmel et al, 1999;Kassiri et al, 2002;Ramakers and Storm, 2002;Sanchez et al, 2002;Varga et al, 2004;Aimond et al, 2005;Tang et al, 2005;Lauver et al, 2006;Wang and Schreurs, 2006;Colinas et al, 2008;Nerbonne et al, 2008). In general, these studies used toxin concentrations of 100 to 200 nM, which in our assay would produce an approximately 20% decrease in Kv4.3 current at ϩ50 mV (Zarayskiy et al, 2005).…”

“…It is one of a diverse group of peptide toxins that form an "inhibitor cystine knot" (ICK) motif (Norton and Pallaghy, 1998). HpTx2 and the nearly identical HpTx3 have been shown to inhibit Kv4-based transient outward currents in the hearts and brains of several mammalian species but to have no apparent effect on other currents, including nonKv4-based transient K ϩ currents, demonstrating the toxin's utility in understanding native transient outward potassium currents (Sanguinetti et al, 1997;Brahmajothi et al, 1999;Guo et al, 1999Guo et al, , 2005Himmel et al, 1999;Kassiri et al, 2002;Ramakers and Storm, 2002;Sanchez et al, 2002;Varga et al, 2004;Aimond et al, 2005;Tang et al, 2005;Lauver et al, 2006;Wang and Schreurs, 2006;Colinas et al, 2008;Nerbonne et al, 2008).…”

Estrogen Differentially Modulates the Cannabinoid- Induced Presynaptic Inhibition of Amino Acid Neurotransmission in Proopiomelanocortin Neurons of the Arcuate Nucleus

“…For example, cannabinoids activate an inwardly rectifying K + channel in AtT20 cells transfected with the CB1 receptor [21, 22], and in oocytes co-expressing the CB1 receptor and the G-protein gated, inwardly rectifying K + channel [23, 24]. Cannabinoids also positively modulate A-type K + currents in cultured hippocampal [25, 26] as well as ARC [27] neurons. Conversely, cannabinoids inhibit Ca 2+ channels in dorsal root ganglion neurons [28], as well as a variety of different cell lines and expression systems [21, 22, 29, 30].…”