Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (␣2-␦-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the ␣2-␦-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.

The voltage-sensitive sodium channel confers electrical excitability on neurons, a fundamental property required for higher processes including cognition. The ion-conducting ␣-subunit of the channel is regulated by two known auxiliary subunits, ␤1 and ␤2. We have identified rat and human forms of an additional subunit, ␤3. It is most closely related to ␤1 and is the product of a separate gene localized to human chromosome 11q23.3. When expressed in Xenopus oocytes, ␤3 inactivates sodium channel opening more slowly than ␤1 does. Structural modeling has identified an amino acid residue in the putative ␣-subunit binding site of ␤3 that may play a role in this difference. The expression of ␤3 within the central nervous system differs significantly from ␤1. Our results strongly suggest that ␤3 performs a distinct neurophysiological function.T he voltage-sensitive sodium channel plays a fundamental role in excitable cells, transiently increasing the sodium permeability of the plasma membrane in response to changes in membrane potential and thus propagating the action potential (1, 2). Not surprisingly, mutations in sodium channel genes are implicated in several pathologies, including epilepsy and cardiac arrhythmias (3-5), and therapeutic drugs, including antiepileptics, local anesthetics, and anticonvulsants (6), act on the channel.In the central nervous system, the channel is conventionally described as a heterotrimer composed of a 260-kDa ␣-subunit, a noncovalently associated 36-kDa ␤1-subunit, and a disulfidelinked 33-kDa ␤2-subunit (2). The ␣-subunit forms the ion pore and is responsible for the voltage-sensitive characteristics of the complex. There are multiple isoforms of the ␣-subunit expressed in different regions of the brain and peripheral nervous system that differ in their kinetic properties (1). The ␤-subunits are auxiliary components acting in a regulatory capacity (7). ␤1 increases the fraction of ␣-subunits operating in a fast gating mode, thus accelerating the activation and inactivation kinetics of the channel and modulating the frequency with which neurons fire (8). The ␤2-subunit is required for the efficient assembly of the channel but has minor effects on gating kinetics. These two ␤-subunits are distantly related by sequence (9).We now report the cloning and analysis of the rat and human forms of a previously uncharacterized sequence that we call ␤3. It is homologous to ␤1, but differs from ␤1 both in its distribution within the brain and in some of its kinetic properties. The discovery of this subunit increases the complexity of the sodium channel and raises further questions about the role of these auxiliary subunits. Materials and MethodsCloning Methodology. We isolated a variant of the rat pheochromocytoma cell line PC12 (termed A35C), which lacks typical neuronal properties (10). To discover previously unidentified neuroendocrine-specific genes, subtractive cloning was used to identify transcripts expressed at a level in the variant cells lower than that in normal PC12 cells. Total RNA wa...

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Burst abdomen and incisional herniation are continuing problems for the general surgeon. A prospective study was carried out to define the extent of the problem. Over five years from 1975 to 1980 a total of 1129 major laparotomy wounds in adults were assessed at regular intervals for 12 months after operation. There were 19 burst abdomens (1-7%) and 84 incisional hernias (74%). The introduction of the mass-closure technique reduced the

Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channel-targeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.