The goal of the present study was to investigate the clinical profile of patients with primary headache syndromes who also suffer from mood disorders. Four-hundred-and-seventy headache outpatients (170M, 300F) and 150 age- and sex-matched healthy subjects were screened using a specific questionnaire that included the Hamilton rating scales for anxiety and depression. The average scores of the Hamilton rating scales for anxiety and depression were significantly higher in headache sufferers (17.4 and 14.2, respectively) than in healthy people (6.8 and 5.7, respectively). The frequency of headache attacks, the history of headaches, and gender (women more than men) were correlated with the score of the Hamilton rating scale for both anxiety and depression. Sixteen headache patients (3.4%) achieved the DSM-IV criteria for major depression or dysthymia versus one among headache-free subjects (0.6%; OR 5.2). Patients suffering from drug-overuse and migraine with aura showed the higher odds ratios (35 and 17, respectively). These results suggest that those headache patients with long history and high frequency of headaches, or patients suffering from migraine with aura and drug-overuse might benefit from psychiatric evaluation.

ATP-sensitive potassium channels (KATP) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated KATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system. AbbreviationsABC, ATP binding cassette; AP, action potential; KATP, ATP-sensitive potassium channel; KCO, ATP-sensitive potassium channel opening drug; PIP2, phosphatidyl 4,5-bisphosphate; SUR, sulphonylurea receptor; VSM, vascular smooth muscle IntroductionTwo independent laboratories can lay claim to having first described the ATP-sensitive potassium channels (KATP; channel nomenclature follows Alexander et al., 2013). Noma (1983) observed the appearance of an outward K + current in heart muscle cells when treated with metabolic poisons or hypoxia. This was reversed by ATP injected into the cell. Similar observations were made by another group (Trube and Hescheler, 1984). Such channels were subsequently described in pancreatic beta cells (Ashcroft et al., 1984), skeletal muscle (Spruce et al., 1985), smooth muscle (Standen et al., 1989) and neurones (Ashford et al., 1988). During this period, the basic electrophysiological and pharmacological properties of the channel were elucidated (Ashcroft, 1988;Noma and Takano, 1991). In inside-out patches in ∼140 mM symmetrical K + concentrations, the single-channel conductance is ohmic with a conductance of 70-80 pS. The lower values sometimes noted in the literature generally have lower and asymmetric K + concentrations. The channel is highly selective for potassium (PNa/PK∼0.01). Activity is inhibited by the application of ATP with a Ki of 10-500 μM with a Hill coefficient of more than 1 (generally around 2) depending on the tissue and recording configuration. The ATP inhibition is not dependent on ATP hydrolysis: it is not reliant on Mg 2+ and ATP can be substituted by non-hydrolysable derivatives. In the absence of magnesium other adenine nucleotides can inhibit channel activity but they are less potent. However, in the presence of Mg 2+ and ATP, ADP is stimulatory. Even at the beginning of the 1990s the channels were known to have a rich pharmacology (see Edwards and Weston, 1993). Sulphonylureas were discovered accidentally when it was noted that the anti-microbial sulphonamides caused hypoglycaemia in animals. It became apparent that stimulation of insulin release from pancreatic beta cells occurred because of inhibition of KATP channels. There is a family of these drugs: the most widely known are the firstgeneration agents (e.g. tolbutamide, chlorpropamide) and the more potent second-generation agents (e.g. glibenclamide, gliclazide, glipizide). Th...

A TP-sensitive potassium channels (K ATP ) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability. 1 K ATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM K ATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM K ATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators. [4][5][6][7] The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2. 8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of K ATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the K ATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of K ATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that K ATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM K ATP channel contributes modestly to vascular control. 10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the K ATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).Abstract-ATP-sensitive potassium channels (K ATP ) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that K ATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that K ATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle K ATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit.

Aims/hypothesisDominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (KATP) channel mutations causing HH in the proband.MethodsWe studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the KATP channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the 86Rb flux assay.ResultsThe mutant channels all showed a lack of 86Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic.Conclusions/interpretationThe phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.