Kegg Pathway: Calcium channel-blocking drugs

Eur J Pharmacol. 2009 Nov 14;
Dhaese I, Van Colen I, Lefebvre RA

Hydrogen sulfide (H(2)S) has been suggested as a gaseous neuromodulator in mammals. The aim of this study was to examine the influence of H(2)S on contractility in mouse distal colon. The effect of sodium hydrogen sulfide (NaHS; H(2)S donor) on prostaglandin F(2alpha) (PGF(2alpha))-contracted circular muscle strips of mouse distal colon was investigated. In addition, tension and cytosolic Calcium concentration ([Ca(2+)](cyt)) in the mouse distal colon strips were measured simultaneously in the presence of NaHS. NaHS caused concentration-dependent relaxation of the pre-contracted mouse distal colon strips. The NaHS-induced relaxation was not influenced by the K(+) channels blockers glibenclamide, apamin, charybdotoxin, barium chloride and 4-aminopyridine. The relaxation by NaHS was also not influenced by the nitric oxide inhibitor L-NAME, by the soluble guanylate cyclase respectively adenylate cyclase inhibitors ODQ and SQ 22536, by the nerve blockers capsazepine, omega-conotoxin and tetrodotoxin or by several channel and receptor blockers (ouabain, nifedipine, 2-aminoethyl diphenylborinate, ryanodine and thapsigargin). The initiation of the NaHS-induced relaxation was accompanied by an increase in [Ca(2+)](cyt), but once the relaxation was maximal and sustained, no change in [Ca(2+)](cyt) was measured. This Calcium desensitization is not related to the best known Calcium desensitizing mechanism as the myosin light chain phosphatase (MLCP) inhibitor calyculin-A and the Rho-kinase inhibitor Y-27632 had no influence. We conclude that NaHS caused concentration-dependent relaxations in mouse distal colon not involving the major known K(+) channels and without a change in [Ca(2+)](cyt). This Calcium desensitization is not related to inhibition of Rho-kinase or activation of MLCP.

Anasthesiol Intensivmed Notfallmed Schmerzther. 2009 Nov; 44(11-12): 736-44
Wörner J, Rukwied R, Konrad C

The sensation of pain arises through stimulation of peripheral nociceptors and is transmitted centrally involving several receptors and ion channels. In addition many endogenous physiologic pain-modulating mechanisms exist. Besides of classical analgesics, numerous other drugs showed analgesic properties based on diverse modes of actions along the pain pathway. These co-analgesics, administered in combination with classical drugs, are able to reduce painful states of different origin. We describe the peripheral action sites of co-analgesics, such as cannabinoids, capsaicin, bisphosphonates, steroids and somatostatin. We also summarise the effect of peripherally and centrally acting ion-channel blockers, e.g. local anaesthetics, carbamazepine and tolperisone working on sodium channels and gabapentin and pregabalin working on Calcium channels. Finally, central analgesic mechanisms are discussed, for instance the inhibition of NMDA-receptors by ketamine or magnesium, the stimulation of alpha2-receptors by clonidine, tizanidine or antidepressants, the activation of GABA-receptors through baclofen and other analgesic mechanisms of i.e. ondansetron and neostigmine.

Cephalalgia. 2009 Dec; 29(12): 1242-58
Storer RJ, Immke DC, Goadsby PJ

Migraine is a common, disabling, neurological problem whose acute management would benefit from the development of purely neurally acting therapies. The trigeminocervical complex is pivotal in nociceptive signaling in migraine, and is an accepted target for putative antimigraine agents. Whole-cell patch-clamp or extracellular recordings were made of trigeminal neurons identified in rat brainstem slices. Bath application of the large conductance Calcium-activated potassium (BKCa) channel opener NS1619 caused a dramatic decrease of cell firing that could be reversed by the co-application of iberiotoxin. NS1619 hyperpolarized the resting membrane potential and reduced the frequency of spontaneous action potentials in these neurons. These data suggest the presence of BKCa channels in the trigeminocervical complex. In vivo in cat L-glutamate-evoked firing was facilitated in nociceptive neurons, also responding to stimulation of the superior sagittal sinus, in the trigeminal nucleus caudalis by the BKCa peptide antagonists, iberiotoxin and slotoxin. Of units tested, 70% responded to microiontophoretic application of the blockers, identifying a subpopulation of trigeminal neurons expressing toxin-sensitive BKCa channels. NS1619 inhibited 74% of cells tested, and this was reversed by slotoxin, suggesting that the action of NS1619 in these cells was mediated through BKCa channels. These data are consistent with the presence of BKCa channels in the trigeminal nucleus caudalis that are potential targets for the development of antimigraine treatments, and may also offer insights into receptor mechanisms involved in sensitization and thus allodynia, in migraine.

PLoS One. 2009; 4(11): e7593
Oh WS, Jeong PY, Joo HJ, Lee JE, Moon YS, Cheon HM, Kim JH, Lee YU, Shim YH, Paik YK

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+) channel blockers suggested that HWY-4213 targets the Calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.

Arch Soc Esp Oftalmol. 2009 Oct; 84(10): 491-500
Muñoz-Negrete FJ, Pérez-López M, Won Kim HR, Rebolleda G

The medical treatment of glaucoma has undergone significant development in recent years. Research in this field is focused on improving pre-existing drugs and on the development of new molecules. In relation to commercial drugs, there is a trend to improve local tolerance, using less toxic preservatives as in the case of sofZIA in travoprost, and eliminating the preservatives as in tafluprost. The development of new, fixed combinations of commercial drugs could also enhance their administration and therapeutic compliance. There is also intense research activity in the search for new therapeutic groups for glaucoma treatment. Calcium channel-blockers such as lomerizine do not seem to affect systemic hypotension, while topical Calcium-blockers like flunarizine and iganidipine are also under research. Endothelin 1 antagonists such as sulfisoxazole and bunazosine could be also useful in the treatment of glaucoma. In the renin angiotensin system, angiotensin (1-7) and olmesartan are under investigation for use in glaucoma patients. Trabecular drugs such as Rho-kinase inhibitors could be effective on the pathogenic mechanism of primary open angle glaucoma. Finally, topical mifepristone, an antagonist of glucocorticoid receptors, is under evaluation for corticosteroid-induced elevated intraocular pressure (Arch Soc Esp Oftalmol 2009; 84: 491-500).

Expert Rev Cardiovasc Ther. 2009 Nov; 7(11): 1349-61
Reboldi G, Gentile G, Angeli F, Verdecchia P

Diabetes causes approximately 2.9 million deaths yearly, mainly through an increased risk of cardiovascular disease. In hypertensive diabetics, blood pressure reduction determines a significantly lower rate of cardiovascular and renal events. Conversely, reaching the generally recommended target of lower than 130/80 mmHg is a difficult challenge and, in most cases, two or more antihypertensive drugs are required. Until recently, there was a general consensus that combination treatment should include a diuretic as one of the two fundamental agents. However, recently published trials using Calcium channel blockers plus renin-angiotensin system-blocking agents showed that such a combination reduces the risk of major cardiovascular events, provides greater renoprotection, and improves metabolic outcomes as compared with diuretic-based combinations. The present review explores the potential for an 'optimal' combination therapy in patients with diabetes mellitus and hypertension, in view of recent experimental and clinical evidence.

Cas Lek Cesk. 2009; 148(8): 370-3
Janota T

Hypertensive crisis is an acute, life-threatening condition associated with a substantial sudden increase in blood pressure. If the increase is accompanied by a damage of brain, cardiovascular system, eye ground or kidneys, it is referred to as an emergent hypertensive situation. In case of complaints comprising chest pain, shortness of breath, headache, epistaxis, weakness, faintness or seizure alone without organ damage, it is referred to as an urgent hypertensive situation. Treatment of emergent situations is parenteral and is conducted under a permanent monitoring in an intensive care unit. Nitrates, urapidil, diuretics, angiotensin-converting enzyme inhibitors, Calcium channel blockers, beta blockers and clonidin are used with respect to organ damage and accompanying diseases. Rate of blood pressure reduction and target values depend on a type of organ damages. An escalation of per oral medication is used in the treatment of urgent situations. Parenteral medication is indicated only in case of failure of this approach.

Indian Pacing Electrophysiol J. 2009; 9(6): 355-9
Bonney WJ, Ceresnak SR, Ira S, Hordof A, Liberman L

Primary tumors of the heart are rare, but they are often associated with refractory arrhythmias. Vascular tumors of the heart comprise a small minority of primary cardiac tumors. In patients with structurally normal hearts, ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT) can be sensitive to adenosine, vagal maneuvers, and Calcium channel blockers. In this report, we describe a case of ventricular tachycardia originating from within a hemangioma in the RVOT that was ultimately controlled with verapamil.

Zhongguo Zhong Yao Za Zhi. 2009 Aug; 34(15): 1959-63
Ji Y, Gao S, Feng X, He L

OBJECTIVE: To study how the way in which betaine promotes the proliferation of mouse spleen lymphocytes is related to Calcium channels. METHOD: BALB/c mice were used for this experiment. Mouse spleen lymphocytes were obtained through in vitro cultivation after they had been separated, and were divided into a negative control group, a Con A group, and 0.04, 0.4, 4, and 20 mmol x L(-1) betaine groups. MTT was used to observe the effect of betaine on the proliferation of mouse spleen lymphocytes; flow cytometry was used to measure the changes in the cell cycle of mouse spleen lymphocytes; and laser confocal scanning microscopy was used to observe the changes in the intracellular [Ca2+]i of mouse spleen lymphocytes after betaine or different Calcium channel blockers were applied. RESULT: Betaine was found to promote the proliferation of mouse spleen lymphocytes 12 h after it had been applied in vitro in concentrations of 4 and 20 mmol x L(-1). It was also found to promote the proliferation of mouse spleen lymphocytes 24 h and 48 h after it had been applied in vitro in concentrations of 0.04, 0.4, 4, and 20 mmol x L(-1), with the effect being most marked for the 4 mmol x L(-1) group 24 h after its application. It was found to facilitate the entry of mouse spleen lymphocytes from the G0/G1 to the S phase 4, 6, 18, and 24 h after it had been applied to mouse spleen lymphocytes in a concentration of 4 mmol x L(-1), with the effect being most marked at 18 h after its application. Intracellular [Ca2+]i in mouse spleen lymphocytes increased significantly (P < 0.01) 6, 12, 18 h after 4 mmol x L(-1) betaine had acted on the lymphocytes, with the effect being most marked at 6 h. The Calcium channel blockers nifidipine, diltiazem, mibefradil, and genistein had no effect on the increase of the intracellular [Ca2+]i in mouse spleen lymphocytes due to the application of betaine, while verapamil, mycifradin, heparin, and procaine could block such increase. CONCLUSION: Betaine facilitates the entry of mouse spleen lymphocytes from the G0/G1 into the S phase by raising the intracellular [Ca2+]i in these cells, thus promoting their proliferation. Intracellular [Ca2+]i increases mainly in two ways: (1) By affecting the alpha1 subunit of the L-type voltage-gated Calcium channel with mediation by G proteins and thus leading to an efflux of intracellular Calcium: (2) By affecting the IP3R and RyR Calcium channels of the intracellular Calcium stores and thus leading to the release of intracellular Calcium.

Health Policy. 2009 Oct 28;
Wettermark B, Godman B, Neovius M, Hedberg N, Mellgren TO, Kahan T

OBJECTIVE: The Swedish Dental and Pharmaceutical Benefits Agency is re-assessing the value of all drugs included in the reimbursement scheme in order to make the most efficient use of resources. Their recent review of antihypertensive drugs included 46 substances with total annual sales of euro230 million (euro25/capita). This resulted in reimbursement restrictions for 26 substances, e.g. all angiotensin receptor blockers (ARBs). METHODS: We used the Swedish prescribed drug register to evaluate the initial effects on prescribing patterns using a before-and-after design, comparing utilization and expenditure with corresponding periods previous years. RESULTS: The proportion of the Swedish population being dispensed antihypertensive drugs increased by 0.5%-units to 16.5% in September-December 2008 compared to the same period in 2007. Patients initiated on ARBs decreased by 24%, whilst increasing for ACE inhibitors (ACEI) and Calcium channel blockers, by 14% and 12%, respectively. The proportion initiated on ARBs prescribed an ACEI within 24 months prior to an ARB increased from 51% to 67%, with a substantial regional variation (extremal quotient 31; coefficient of variation 36%). The total expenditure decreased by 4.7% to euro73 million in September-December 2008 compared to the same period in 2007. CONCLUSIONS: Reimbursement restrictions had a positive impact on enhancing the efficiency of antihypertensive prescribing. Resources released can be used to improve care in the future.

Invest New drugs. 2009 Oct 30;
Viale M, Cordazzo C, de Totero D, Budriesi R, Rosano C, Leoni A, Ioan P, Aiello C, Croce M, Andreani A, Rambaldi M, Russo P, Chiarini A, Spinelli D

We report herein the reversal of multidrug resistance-1 (MDR1) in A2780/DX3 cells by the two nifedipine-like compounds 1 and 2 that are part of a library of 1,4-dihydropyridines (1,4-DHPs) Calcium-channel modulators bearing in C-4 a different substituted imidazo[2,1-b]thiazole system. By methylthiazol tetrazolium (MTT) assay, cytofluorimetry, and fluorescence microscopy we evaluated their ability to reverse MDR in our cell system. Moreover, together with compound 3 (the diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one) we analyzed their ability to potentiate the triggering of apoptosis after exposure to doxorubicin, through the nuclear morphological analysis after 4',6-diamidino-2-phenylindole (DAPI), the fluorescein isothiocyanate (FITC)-Annexin-V/propidium iodide (PI) staining and the caspase activity determination. Our results demonstrate that compounds 1 and 2, at concentrations showing a very low (5%) or absent inhibition of cell proliferation, in combination with doxorubicin enhance its antiproliferative activity (from 30% to 54% IC(50) reduction) in A2780/DX3 cells through an increase of doxorubicin intracellular accumulation. These compounds together with compound 3, which has already been demonstrated to act as a potent inhibitor of MDR1 function, were also able to significantly potentiate the activation of the apoptosis machinery triggered by the exposure to doxorubicin. In conclusion, our results identify two new molecules structurally related to the Calcium-channel blocker nifedipine, but characterized by a very low LTCC blockers activity, able to potentiate the antiproliferative and apoptotic activities of doxorubicin through an increase of its intracellular concentration likely caused by the inhibition of MDR1 function.

Zhongguo Zhen Jiu. 2009 Oct; 29(10): 807-9
Li H

OBJECTIVE: To search for an effective therapy for cold erythema multiforme in ham. METHODS: One hundred and eighty cases with cold erythema multiforme in ham were randomly divided into a Santong group (n=90) and a western medicine group (n=90). The Santong group was treated by He's Santong needling methods and Huantiao (GB 30), Fengshi (GB 31), Zusanli (ST 36), etc. were selected. The western medicine group was treated by oral administration of Cinnarizine, Cyproheptadine and Vitamin E. Two weeks later, their therapeutic effects were observed. RESULTS: The cured rate was 68.9% and the recurrence rate was 11.3% in the Santong group, and 33.3% and 53.3% in the western medicine group, with significant differences in the cured rate and the recurrence rate between the two groups (both P<0.01). CONCLUSION: He's Santong needling methods can increase the cured rate and reduce the recurrence rate of cold erythema multiforme in ham.

Mol Neurodegener. 2009; 4: 44
Wildburger NC, Lin-Ye A, Baird MA, Lei D, Bao J

ABSTRACT: Cognitive and functional decline with age is correlated with deregulation of intracellular Calcium, which can lead to neuronal death in the brain. Previous studies have found protective effects of various Calcium channel blockers in pathological conditions. However, little has been done to explore possible protective effects of blockers for T-type Calcium channels, which forms a family of FDA approved anti-epileptic drugs. In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type Calcium channel antagonists. The family of low-voltage activated, or T-type Calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha1G, alpha1H, and alpha1I. Among these three subunits, alpha1H is highly expressed in hippocampus and certain cortical regions. However, T-type Calcium channel blockers can protect neurons derived from alpha1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the alpha1H subunit. In addition, blockers for T-type Calcium channels were not able to confer any protection to neurons in long-term cultures, while blockers of L-type Calcium channels could protect neurons. These data indicate a new function of blockers for T-type Calcium channels, and also suggest different mechanisms to regulate neuronal survival by Calcium signaling pathways. Thus, our findings have important implications in the development of new treatment for age-related neurodegenerative disorders.

Heart. 2009 Oct 26;
Chapman N, Schachter M

Antiplatelet therapy plays a pivotal role in modern management of coronary artery disease and use of clopidogrel has facilitated the emergence of intravascular stenting as common cardiological practice. However, clopidogrel responsiveness is heterogeneous within the population, with a sizable proportion seemingly non-responsive to its antiplatelet effects and at higher risk of cardiovascular events as a result [1, 2].

Transplant Proc. 2009 Oct; 41(8): 3069-72
Małyszko J, Małyszko J, Bachórzewska-Gajewska H, Poniatowski B, Dobrzycki S, Mysliwiec M

BACKGROUND: Hypertension is a widely accepted risk factor for coronary artery disease (CAD), chronic heart failure, and chronic kidney disease (CKD). In kidney transplant recipients, the prevalence of hypertension is 60% to 80%. OBJECTIVE: To assess the prevalence of target blood pressure in 2 high-risk populations: patients with CAD and kidney allograft recipients. PATIENTS AND METHODS: The study included 520 patients with CAD and 150 kidney allograft recipients. In the CAD population, 30% of patients had diabetes mellitus and 33% had CKD. In kidney allograft recipients, 52% had diabetes (15%) or CKD. Hypertension was diagnosed and treated in 72% of patients with CAD and 90% of kidney allograft recipients. In the CAD population without diabetes but with CKD, target blood pressure was achieved in 47% compared with 31% in the CKD population. Treatment included angiotensin-converting enzyme (ACE) inhibitors in 72% of patients, Calcium channel blockers in 28%, diuretic agents in 27%, and beta-blockers in 89%. In allograft recipients, more than 60% required 3 or more hypotension agents. Only 40% demonstrated target blood pressure. In the latter group, the most commonly used hypotension agents were ACE inhibitors in 38%, Calcium channel blockers in 84%, diuretic agents in 51%, beta-blockers in 68%, and alpha-blockers in 15%. CONCLUSION: Both cohorts demonstrated a high prevalence of hypertension. Despite polytherapy, optimal blood pressure control was not achieved in most patients. Greater efforts should be expended to optimize blood pressure control, in particular in the presence of comorbidities. In transplant recipients, beta-blockers are widely used, whereas ACE inhibitors are used infrequently.

Am J Physiol Heart Circ Physiol. 2009 Oct 30;
Bishara NB, Ding H

Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease and, in the current study, the link to glucose-induced abnormal intracellular Calcium (Ca(2+)i) homeostasis was explored in bovine aortic endothelial cells (BAECs) in high glucose (HG) (25 mmol/L) versus control (low glucose, LG) (5.5 mmol/L). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4 or TRPC6 expression, was significantly increased in HG vs. LG at 72 h. HG for 4, 24 and 72 h did not change basal Ca(2+)i or ATP-induced Ca(2+)i release, however, the amplitude of sustained Ca(2+)i was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but non-specific, TRPC blockers, gadolinium (Gd(3+)), SKF96365 and 2-aminoethoxydiphenyl borate (2-APB). Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca(2+) entry in BAECs. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca(2+) entry and endothelial dysfunction requires further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function. Key words: Bovine aorta endothelial cells, hyperglycemia, transient receptor potential channels, store-operated Calcium entry.

Med J Malaysia. 2009 Mar; 64(1): 3-11
Ong HT, Rozina G

Clin Interv Aging. 2009; 4: 379-89
Stokes GS

Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and 'white coat effect'. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a Calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension-hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.

J Biol Chem. 2009 Oct 22;
Wu ZZ, Li DP, Chen SR, Pan HL

Aminopyridines such as 4-aminopyridine (4-AP) are widely used as voltage-activated K+ (Kv) channel blockers and can improve neuromuscular function in patients with spinal cord injury, myasthenia gravis, or multiple sclerosis. Here we present novel evidence that 4-AP and several of its analogues directly stimulate high voltage-activated Ca2+ channels (HVACCs) in native neurons. 4-AP, 4-(aminomethyl)pyridine, 4-(methylamino)pyridine, and 4-di(methylamino)pyridine profoundly increase HVACC, but not T-type, currents in dissociated neurons from the rat dorsal root ganglion, superior cervical ganglion, and hippocampus. The widely used Kv channel blockers, including tetraethylammonium, alpha-dendrotoxin, phrixotoxin-2, and BDS-I, do not mimic or alter the effect of 4-AP on HVACCs. In HEK293 cells expressing various combinations of N-type (Cav2.2) channel subunits, 4-AP potentiates Ca2+ currents primarily through the intracellular beta3 subunit. In contrast, 4-AP has no effect on Cav3.2 channels expressed in HEK293 cells. Furthermore, blocking Kv channels does not mimic or change the potentiating effects of 4-AP on neurotransmitter release from sensory and motor nerve terminals. Thus, our findings challenge the conventional view that 4-AP facilitates synaptic and neuromuscular transmission by blocking Kv channels. Aminopyridines can directly target HVACCs to potentiate neurotransmitter release independent of Kv channels.

J Neurosci. 2009 Oct 21; 29(42): 13328-37
Shahidullah M, Reddy S, Fei H, Levitan IB

Molecular details of ion channel interactions with modulatory subunits have been investigated widely in transfected cells, but the physiological roles of ion channel modulatory protein complexes in native neurons remain largely unexplored. The Drosophila large-conductance Calcium-activated potassium channel (dSlo) binds to and is modulated by its binding partner Slob. We have constructed flies in which Slob expression is manipulated by P-element mutagenesis, or by transgenic expression of Slob protein or Slob-RNAi. In vivo recordings of both macroscopic and single dSlo channel currents in identified neurosecretory neurons in the pars intercerebralis (PI) region of the Drosophila brain reveal that whole-cell potassium current and properties of single dSlo channels are modulated by Slob expression level. Furthermore, Slob genotype influences action potential duration in vivo. This unprecedented combination of current-clamp, macroscopic-current, and single-channel recordings from neurons in brains of living flies defines a critical role for an ion channel modulatory protein complex in the control of neuronal excitability. We show further that Slob-null flies exhibit significantly longer lifespan than controls under conditions of complete food deprivation. Crosses with deficiency lines demonstrate that this enhanced resistance to starvation-induced death maps close to the slob locus. Together, these results indicate that Slob may serve a novel regulatory function in feeding behavior, possibly by influencing the excitability of the PI neurons.