Atrial natriuretic peptide (ANP) is a polypeptide hormone whose effects include the induction of diuresis, natriuresis and vasorelaxation. One of the earliest events following binding of ANP to receptors on target cells is an increase in cyclic GMP concentration, indicating that this nucleotide might act as a mediator of the physiological effects of the hormone. Guanylate cyclase exists in at least two different molecular forms: a soluble haem-containing enzyme consisting of two subunits and a non-haem-containing transmembrane protein having a single subunit. It is the membrane form of guanylate cyclase that is activated following binding of ANP to target cells. We report here the isolation, sequence and expression of a complementary DNA clone encoding the membrane form of guanylate cyclase from rat brain. Transfection of this cDNA into cultured mammalian cells results in expression of guanylate cyclase activity and ANP-binding activity. The ANP receptor/guanylate cyclase represents a new class of mammalian cell-surface receptors which contain an extracellular ligand-binding domain and an intracellular guanylate cyclase catalytic domain.

The Ca 2؉ channel ␣1A-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca 2؉ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. ␣1A-Subunits are thought to support both P-and Q-type Ca 2؉ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca 2؉ delivery system at excitatory nerve terminals. We generated ␣1A-deficient mice (␣1A ؊͞؊ ) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying Ϸ3-4 weeks after birth. P-type currents in Purkinje neurons and P-and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca 2؉ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in ␣1A ؊͞؊ hippocampal slices persisted despite the lack of P͞Q-type channels but showed enhanced reliance on N-type and R-type Ca 2؉ entry. The ␣1A ؊͞؊ mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in ␣1A. The ␣ 1A -subunit, the most abundant ␣ 1 -subunit in vertebrate brain (1), mediates Ca 2ϩ influx across presynaptic and somatodendritic membranes, thereby triggering fast neurotransmitter release and other key neuronal responses (2-5). Because of its high expression levels in the brain, the ␣ 1A -subunit was the first representative of its subclass to be isolated by cDNA cloning (1, 6). This predominantly neuronal subclass also includes ␣ 1B (N-type Ca 2ϩ channel) and ␣ 1E [possibly R-type Ca 2ϩ channel (7-9)] and is referred to as ABE or Ca V 2. There is no information to date on the behavioral or electrophysiological consequences of deleting a member of the ABE subfamily.␣ 1A Transcripts are widely distributed in rat (10) and human brain (11), most prominently in cell body layers in cerebellum and hippocampus. At the subcellular level, ␣ 1A immunoreactivity has been found in cell bodies, dendrites, and presynaptic terminals (12). Less clear has been the role of ␣ 1A in supporting Ca 2ϩ channel components defined by biophysical and pharmacological criteria. In either Xenopus oocytes (13, 14) or HEK293 cells (15), expression of ␣ 1A -subunits along with ancillary ␣ 2 ͞␦-and ␤-subunits generated currents with properties closely resembling the Q-type current found in cerebellar granule cells (8) and much less the P-type current first described in cerebellar Purkinje neurons by Llinás and colleagues (16,17). Unlike native P-type channels (18), the expressed currents showed pronounced inactivation during sustained depolarizations and responded to -agatoxin IVA (-Aga-IVA) at half-blocking doses of Ϸ100 nM, not Ϸ1 nM (13). Various explanations for the discrepancies have been advanced...

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ehaviors related to self-regulation, such as substance use disorders or antisocial behaviors, have far-reaching consequences for affected individuals, their families, communities and society at large 1,2 . Collectively, this group of correlated traits are classified as externalizing 3 . Twin studies have demonstrated that externalizing liability is highly heritable (~80%) 4,5 . To date, however, no large-scale molecular genetic studies have utilized the extensive degree of genetic overlap among externalizing traits to aid gene discovery, as most studies have focused on individual disorders 6 . For many high-cost, high-risk behaviors with an externalizing component-opioid use disorder and suicide attempts 7 being salient examples-there are limited genotyped cases available for gene discovery 8,9 .A complementary strategy to the single-disease approach is to study the shared genetic architecture across traits in multivariate analyses, which boosts statistical power by pooling data across

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