Antibodies to ANNA-1 are consequently, most commonly found in patients with small cell lung cancer with associated paraneoplastic gastrointestinal dysmotility. are known to target onconeural antigens shared by enteric neurons and tumor cells suggesting that the antibody was generated against the tumor antigen with the enteric neuron as the innocent bystander [1]. The antigens for these antibodies may be localized to the nucleus, plasma membrane or the cytoplasm. The most common neuronal autoantibody associated with a paraneoplastic dysmotility is the type 1 R 80123 antineuronal nuclear antibody (ANNA-1) [1,2]. ANNA-1 recognizes the nuclear protein Hu which belongs to a family of conserved RNA binding proteins that includes HuC, HuD, HuR and Hel-N1. These proteins are expressed in the neurons of the central, peripheral and enteric nervous system, with the exception of HuR which is ubiquitously expressed in proliferating cells [3]. The tumor that most commonly expresses ANNA-1 is small cell lung cancer [4]. Other tumors that may express ANNA-1 include breast, prostate, ovarian carcinomas and lymphomas [5]. Antibodies to ANNA-1 are consequently, most commonly found in patients with small cell lung cancer with associated paraneoplastic gastrointestinal dysmotility. Although there is a very strong association between the presence of ANNA-1 in the setting of a gastrointestinal motility disorder and the presence of an occult or manifest tumor, the exact mechanism by which ANNA-1 antibodies cause enteric neuronal dysfunction is still unclear as the proteins to which the antibody is directed are not expressed on the cell membrane. However, there is some evidence that the antibodies may directly influence motility. A preliminary study in guinea pig ileum suggested that anti-Hu antibodies impair the ascending excitatory reflex and therefore peristalsis. Enteric neuronal degeneration has also been reported in patients with paraneoplastic dysmotility as a possible pathogenetic mechanism [7]. Anti HuD positive sera from patients with paraneoplastic gut dysmotility disorder as well as commercial Anti HuD antibodies were shown to induce apoptosis in a human neuroblastoma cell line (SH-Sy5Y) as well as guinea pig cultured myenteric neurons. The authors further demonstrated that the apoptosis was dependent on mitochondria as evidenced by the specific activation of effector caspsase 3 and the cytochrome c-dependent proapoptotic messenger apaf-1 [8]. Mitochondrial dysfunction leading to subsequent neuronal injury is well described and has also been implicated in dorsal root ganglion apoptosis in streptozocin- induced diabetes in rats [9]. Pardi et al described a patient with sudden onset of gastroparesis and small bowel dysfunction and the presence of high circulating levels of ANNA-1 [6]. This patient was subsequently found to have decreased and disorganized interstitial cells of Cajal networks and a small cell lung cancer expressing c-Kit, also expressed on interstitial cells of Cajal. Another nuclear autoantigen associated with disease is Ri, expressed in neurons of the central nervous system, small cell lung cancer and some breast cancer cells [10]. Formation of type 2 anti neuronal nuclear antibodies (ANNA-2 or anti-Ri) is far less common than anti Hu and is usually associated with neurological symptoms from midbrain, brain stem, cerebellar R 80123 or spinal cord dysfunction [11]. ANNA-2 has not been associated with gastrointestinal dysmotility. == Calcium channel antibodies == The second most commonly reported antibodies in patients with paraneoplastic dysmotility target voltage-activated calcium channels. Calcium channels were originally classified based on pharmacology as L, N, P/Q, R, and T channels, a classification still used today. This nomenclature corresponds to the current accepted nomenclature that classifies voltage-gated Ca2+channels Rabbit Polyclonal to CCKAR into Cav1.1-Cav1.4 (L-type Ca2+channels), Cav2.1 (P/Q), Cav2.2 (N), Cav2.3 (R), and Cav3.1- Cav3.3 (T) based on the amino acid sequence of the alpha 1 subunit (the pore forming subunit) of the channel. P or Q type calcium ion R 80123 channels regulate acetylcholine release at the neuromuscular junction as well as central neurotransmission. N type calcium channels are particularly involved in cerebrocortical, cerebellar, spinal and autonomic neurotransmission. Both channel types are expressed in small.