In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment [1][2][3][4][5][6][7] . On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive 8 . Furthermore, pupil reflex 8 , light-induced phase delays of the circadian clock 9,10 and period lengthening of the circadian rhythm in constant light 9,10 are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype 11 , and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells 7 . We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions. © 2003 Nature Publishing GroupCorrespondence and requests for materials should be addressed to K.-W.Y. (kwyau@mail.jhmi.edu). Supplementary Information accompanies the paper on www.nature.com/nature. Competing interests statementThe authors declare that they have no competing financial interests. 8 . In independently produced melanopsin-knockout mice, others have found that the ability of light to phase-delay and lengthen the period of the circadian rhythm is also diminished 9,10 . For the pupil reflex, this photic response can be quantitatively accounted for by a functional complementarity between the rod-cone system and the melanopsin system, without the need to invoke any additional light-detection system 8 . Nonetheless, the proposal has persisted that cryptochromes-flavoproteins reported to have a direct light-detecting role in Drosophila 12,13 -may have the same function in mammals [14][15][16] despite earlier evidence to the contrary 17 . To settle this question, we first examined the action spectrum for phase-shifting the circadian rhythm in mice lacking rod and cone photoreceptors (rd/rd cl) 18 . Next, we generated triple-knockout mice lacking all confirmed photodetection systems-Opn4 −/− Gnat1 −/− Cnga3 −/− (melanopsin (also known as opsin 4), guanine nucleotide-binding protein α-transducin 1 (also known as rod transducin α-subunit, or Trα) and cyclic GMP-gated channel A-subunit 3, respectively)-and tested these animals for pupil reflex, circadian photo-entrainment and the masking response to light. NIH Public AccessIrradiance-response relations for the light-induced phase shifting of the circadian rhythm of l...

We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.)

Pacemaker activity of spontaneously active neurons and heart cells is controlled by a depolarizing, mixed Na+/K+ current, named Ih (or I(f) in the sinoatrial node of the heart). This current is activated on hyperpolarization of the plasma membrane. In addition to depolarizing pacemaker cells, Ih is involved in determining the resting membrane potential of neurons and provides a mechanism to limit hyperpolarizing currents in these cells. Hormones and neurotransmitters that induce a rise in cyclic AMP levels increase Ih by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates Ih. Here we report the molecular cloning and functional expression of the gene encoding a hyperpolarization-activated cation channel (HAC1) that is present in brain and heart. This channel exhibits the general properties of Ih channels. We have also identified full-length sequences of two related channels, HAC2 and HAC3, that are specifically expressed in the brain, indicating the existence of a family of hyperpolarization-activated cation channels.

Letter to the Editorshaping the action potential and controlling patterns of Nomenclature of Voltage-Gated repetitive firing. Calcium ChannelsAs new Ca 2ϩ channel genes are cloned, it is apparent that these two alphabetical nomenclatures will overlap at ␣ 1L , which may not mediate an L-type Ca 2ϩ current and Voltage-gated Ca 2ϩ channels mediate calcium influx in therefore may create confusion. Moreover, the present response to membrane depolarization and regulate inalphabetical nomenclature does not reveal the structural tracellular processes such as contraction, secretion, relationships among the ␣ 1 subunits, which can be neurotransmission, and gene expression. They are memgrouped into three families: (1) ␣ 1S , ␣ 1C , ␣ 1D , and ␣ 1F ; (2) bers of a gene superfamily of transmembrane ion chan-␣ 1A , ␣ 1B , and ␣ 1E ; and (3) ␣ 1G , ␣ 1H , and ␣ 1I . The complete nel proteins that includes voltage-gated K ϩ and Na ϩamino acid sequences of these ␣ 1 subunits are more channels. The Ca 2ϩ channels that have been characterthan 70% identical within a family but less than 40% ized biochemically are complex proteins composed of identical among families. These family relationships are four or five distinct subunits, which are encoded by illustrated for the more conserved transmembrane and multiple genes. The ␣ 1 subunit of 190-250 kDa is the pore domains in Figure 1. Division of calcium channels largest subunit, and it incorporates the conduction pore, into these three families is phylogenetically ancient, as the voltage sensor and gating apparatus, and the known representatives of each are found in the C. elegans gesites of channel regulation by second messengers, nome. Ideally, a nomenclature for Ca 2ϩ channel ␣ 1 subdrugs, and toxins. An intracellular ␤ subunit and a transunits should provide a systematic organization based on membrane, disulfide-linked ␣ 2 ␦ subunit complex are their structural relationships and should be coordinated components of most types of Ca 2ϩ channels. A ␥ subunit with nomenclatures for the other families of voltagehas also been found in skeletal muscle Ca 2ϩ channels, gated ion channels of different ionic selectivities (ie., K ϩ and related subunits are expressed in heart and brain. and Na ϩ ). Although these auxiliary subunits modulate the proper-For these reasons, we wish to propose a new nomenties of the channel complex, the pharmacological and clature of voltage-gated Ca 2ϩ channels (Table 1), which electrophysiological diversity of Ca 2ϩ channels arises is more systematic and mimics the well-defined K ϩ primarily from the existence of multiple forms of ␣ 1 subchannel nomenclature (Chandy et al., 1991). This nounits. Mammalian ␣ 1 subunits are encoded by at least menclature uses a numerical system (K V 1.1, K V 2.1, K V 3.1, ten distinct genes. Historically, various names have etc.) to define families and subfamilies of K ϩ channels been given to the corresponding gene products, giving based on similarities in amino acid sequences. In a simirise to distinct and sometimes confusing nome...

Hyperpolarization-activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. The contributions of the four individual HCN channel isoforms (HCN1±4) to these diverse functions are not known. Here we show that HCN2-de®cient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2-null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocytespeci®c deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results de®ne the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.